Cyclopropylamines as lsd1 inhibitors

ABSTRACT

The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

FIELD OF THE INVENTION

The present invention relates to enzyme inhibitors, which selectivelymodulate demethylase, and uses therefor. Particular embodimentscontemplate compounds and disease indications amenable to treatment bymodulation of lysine specific demethylase-1 (LSD1).

BACKGROUND OF THE INVENTION

Epigenetic modifications can impact genetic variation but, whendysregulated, can also contribute to the development of various diseases(Portela, A. and M. Esteller, Epigenetic modifications and humandisease. Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M.van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p.2315-35). Recently, in depth cancer genomics studies have discoveredmany epigenetic regulatory genes are often mutated or their ownexpression is abnormal in a variety of cancers (Dawson, M. A. and T.Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012.150(1): p. 12-27; Waldmann, T. and R. Schneider, Targeting histonemodifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2):p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genomeand epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigeneticregulators function as cancer drivers or are permissive fortumorigenesis or disease progression. Therefore, deregulated epigeneticregulators are attractive therapeutic targets.

One particular enzyme which is associated with human diseases is lysinespecific demethylase-1 (LSD1), the first discovered histone demethylase(Shi, Y., et al., Histone demethylation mediated by the nuclear amineoxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists ofthree major domains: the N-terminal SWIRM which functions in nucleosometargeting, the tower domain which is involved in protein-proteininteraction, such as transcriptional co-repressor, co-repressor ofRE1-silencing transcription factor (CoREST), and lastly the C terminalcatalytic domain whose sequence and structure share homology with theflavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e.,MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoRESTselectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p.20070-4; Anand, R. and R. Marmorstein, Structure and mechanism oflysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p.35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structureand mechanism of human lysine-specific demethylase-1. Nat Struct MolBiol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure ofhuman histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad SciUSA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree ofhomology with another lysine specific demethylase (LSD2) (Karytinos, A.,et al., A novel mammalian flavin-dependent histone demethylase. J BiolChem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism ofaction is conserved in two isoforms, the substrate specificities arethought to be distinct with relatively small overlap. The enzymaticreactions of LSD1 and LSD2 are dependent on the redox process of FAD andthe requirement of a protonated nitrogen in the methylated lysine isthought to limit the activity of LSD1/2 to mono- and di-methylated atthe position of 4 or 9 of histone 3 (H3K4 or H3K9). These mechanismsmake LSD1/2 distinct from other histone demethylase families (i.e.Jumonji domain containing family) that can demethylate mono-, di-, andtri-methylated lysines through alpha-ketoglutarate dependent reactions(Kooistra, S. M. and K. Helin, Molecular mechanisms and potentialfunctions of histone demethylases. Nat Rev Mol Cell Biol, 2012. 13(5):p. 297-311; Mosammaparast, N. and Y. Shi, Reversal of histonemethylation: biochemical and molecular mechanisms of histonedemethylases. Annu Rev Biochem, 2010. 79: p. 155-79).

Methylated histone marks on K3K4 and H3K9 are generally coupled withtranscriptional activation and repression, respectively. As part ofcorepressor complexes (e.g., CoREST), LSD1 has been reported todemethylate H3K4 and repress transcription, whereas LSD1, in nuclearhormone receptor complex (e.g., androgen receptor), may demethylate H3K9to activate gene expression (Metzger, E., et al., LSD1 demethylatesrepressive histone marks to promote androgen-receptor-dependenttranscription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al.,Androgen receptor coactivators lysine-specific histone demethylase 1 andfour and a half LIM domain protein 2 predict risk of prostate cancerrecurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests thesubstrate specificity of LSD1 can be determined by associated factors,thereby regulating alternative gene expressions in a context dependentmanner. In addition to histone proteins, LSD1 may demethylatenon-histone proteins. These include p53 (Huang, J., et al., p53 isregulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p.105-8), E2F (Kontaki, H. and I. Talianidis, Lysine methylation regulatesE2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60), STAT3 (Yang,J., et al., Reversible methylation of promoter-bound STAT3 byhistone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p.21499-504), Tat (Sakane, N., et al., Activation of HIV transcription bythe viral Tat protein requires a demethylation step mediated bylysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p.e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S.,et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1promotes cell cycle progression in cancer cells. Cancer Res, 2011.71(3): p. 655-60). The lists of non-histone substrates are growing withtechnical advances in functional proteomics studies. These suggestadditional oncogenic roles of LSD1 beyond in regulating chromatinremodeling. LSD1 also associates with other epigenetic regulators, suchas DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysinedemethylase LSD1 (KDM1) is required for maintenance of global DNAmethylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases(HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complexcontaining histone deacetylase mediates repression of neuronal-specificgenes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., etal., Functional interplay between histone demethylase and deacetylaseenzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al.,CoREST is an integral component of the CoREST-human histone deacetylasecomplex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). Theseassociations augment the activities of DNMT or HDACs. LSD1 inhibitorsmay therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed,preclinical studies have shown such potential already (Singh, M. M., etal., Inhibition of LSD1 sensitizes glioblastoma cells to histonedeacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H.,et al., Synergistic re-activation of epigenetically silenced genes bycombinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One,2013. 8(9): p. e75136).

LSD1 has been reported to contribute to a variety of biologicalprocesses, including cell proliferation, epithelial-mesenchymaltransition (EMT), and stem cell biology (both embryonic stem cells andcancer stem cells) or self-renewal and cellular transformation ofsomatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1(LSD1): A potential molecular target for tumor therapy. Crit RevEukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histonedemethylase LSD1 regulates neural stem cell proliferation. Mol CellBiol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C.Izpisua Belmonte, LSD1 and pluripotency: a new player in the network.Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSD1 regulatesthe balance between self-renewal and differentiation in human embryonicstem cells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancerstem cells or cancer initiating cells have some pluripotent stem cellproperties that contribute the heterogeneity of cancer cells. Thisfeature may render cancer cells more resistant to conventionaltherapies, such as chemotherapy or radiotherapy, and then developrecurrence after treatment (Clevers, H., The cancer stem cell: premises,promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C.Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013.13(10): p. 727-38). LSD1 was reported to maintain an undifferentiatedtumor initiating or cancer stem cell phenotype in a spectrum of cancers(Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 ConfersSensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p.445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitorsselectively target cancer cells with pluripotent stem cell properties.Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs)are an example of neoplastic cells that retain some of their lessdifferentiated stem cell like phenotype or leukemia stem cell (LSC)potential. Analysis of AML cells including gene expression arrays andchromatin immunoprecipitation with next generation sequencing (ChIP-Seq)revealed that LSD1 may regulate a subset of genes involved in multipleoncogenic programs to maintain LSC (Harris, W. J., et al., The histonedemethylase KDMJA sustains the oncogenic potential of MLL-AF9 leukemiastem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al.,Inhibition of the LSD1 (KDM1A) demethylase reactivates theall-trans-retinoic acid differentiation pathway in acute myeloidleukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggestpotential therapeutic benefit of LSD1 inhibitors targeting cancershaving stem cell properties, such as AMLs.

Overexpression of LSD1 is frequently observed in many types of cancers,including bladder cancer, NSCLC, breast carcinomas, ovary cancer,glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing'ssarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostatecancer, esophageal squamous cell carcinoma, and papillary thyroidcarcinoma. Notably, studies found over-expression of LSD1 wassignificantly associated with clinically aggressive cancers, forexample, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer,ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. Inthese studies, either knockdown of LSDlexpression or treatment withsmall molecular inhibitors of LSD1 resulted in decreased cancer cellproliferation and/or induction of apoptosis. See, e.g., Hayami, S., etal., Overexpression of LSD1 contributes to human carcinogenesis throughchromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p.574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation,migration and invasion in non-small cell lung cancer. PLoS One, 2012.7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1(Lysine-specific demethylase 1) during tumour progression frompre-invasive to invasive ductal carcinoma of the breast. BMC ClinPathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1(LSD1) is highly expressed in ER-negative breast cancers and a biomarkerpredicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20;Konovalov, S. and I. Garcia-Bassets, Analysis of the levels oflysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors andthe effects of chemical LSD1 inhibitors in ovarian cancer cell lines. JOvarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a noveltherapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1):p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modificationcontributes to proliferation and metastasis of colon cancer. Br JCancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al.,Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed andis an epigenetic drug target in chondrosarcoma, Ewing's sarcoma,osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7;Schulte, J. H., et al., Lysine-specific demethylase 1 is stronglyexpressed in poorly differentiated neuroblastoma: implications fortherapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., Theemerging role of histone lysine demethylases in prostate cancer. MolCancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations andchanges in expression of histone demethylases in prostate cancer.Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression oflysine-specific demethylase 1 correlates with poor prognosis of patientswith esophageal squamous cell carcinoma. Biochem Biophys Res Commun,2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expressionof RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol,2013. 54(3): p. 499-503.

Recently, the induction of CD86 expression by inhibiting LSD1 activitywas reported (Lynch, J. T., et al., CD86 expression as a surrogatecellular biomarker for pharmacological inhibition of the histonedemethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1):p. 104-6). CD86 expression is a marker of maturation of dendritic cells(DCs) which are involved in antitumor immune response. Notably, CD86functions as a co-stimulatory factor to activate T cell proliferation(Greaves, P. and J. G. Gribben, The role of B7 family molecules inhematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D.B. Flies, Molecular mechanisms of T cell co-stimulation andco-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).

In addition to playing a role in cancer, LSD1 activity has also beenassociated with viral pathogenesis. Particularly, LSD1 activity appearsto be linked with viral replications and expressions of viral genes. Forexample, LSD1 functions as a co-activator to induce gene expression fromthe viral immediate early genes of various type of herpes virusincluding herpes simplex virus (HSV), varicella zoster virus (VZV), andβ-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting theJMJD2 histone demethylases to epigenetically control herpesvirusinfection and reactivation from latency. Sci Transl Med, 2013. 5(167):p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1blocks alpha-herpesvirus lytic replication and reactivation fromlatency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1inhibitor showed antiviral activity by blocking viral replication andaltering virus associated gene expression.

Recent studies have also shown that the inhibition of LSD1 by eithergenetic depletion or pharmacological intervention increased fetal globingene expression in erythroid cells (Shi, L., et al., Lysine-specificdemethylase 1 is a therapeutic target for fetal hemoglobin induction.Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependentsilencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad SciUSA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would bepotentially therapeutically beneficial for the disease ofβ-globinopathies, including β-thalassemia and sickle cell disease wherethe production of normal β-globin, a component of adult hemoglobin, isimpaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal toadult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643;Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetalhemoglobin: prospects for new therapies for the beta-globin disorders.Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition maypotentiate other clinically used therapies, such as hydroxyurea orazacitidine. These agents may act, at least in part, by increasingγ-globin gene expression through different mechanisms.

In summary, LSD1 contributes to tumor development by altering epigeneticmarks on histones and non-histone proteins. Accumulating data havevalidated that either genetic depletion or pharmacological interventionof LSD1 normalizes altered gene expressions, thereby inducingdifferentiation programs into mature cell types, decreasing cellproliferation, and promoting apoptosis in cancer cells. Therefore, LSD1inhibitors alone or in combination with established therapeutic drugswould be effective to treat the diseases associated with LSD1 activity.

SUMMARY OF THE INVENTION

The present invention is directed to, inter alia, a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of Formula I and at least onepharmaceutically acceptable carrier.

The present invention is further directed to a method of inhibiting LSD1comprising contacting the LSD1 with a compound of Formula I.

The present invention is further directed to a method of treating anLSD1-mediated disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION

The present invention provides, inter alia, LSD1-inhibiting compoundssuch as a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon        and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring B is 4-10 membered heterocycloalkyl having carbon and 1, 2,        or 3 heteroatoms selected from N, O, and S;    -   ring C is (1) C₆₋₁₀ aryl, (2) C₃₋₁₀ cycloalkyl, (3) 5-10        membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms        selected from N, O, and S, or (4) 4-20 membered heterocycloalkyl        having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O,        and S;    -   wherein L is substituted on any ring-forming atom of ring B        except the ring-forming atom of ring B to which R^(Z) is bonded;    -   L is C₁₋₄ alkylene, —C(═O)—, —C(═O)O—, —C(═O)NR⁷—, O, NR′,        —S(O)₂—, —S(O)—, or —S(O)₂NR⁷—;    -   each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),        C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),        OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),        C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),        NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d),        S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,        CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),        OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),        NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),        NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),        S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);    -   R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),        C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),        NR^(c1)R^(d1), NR^(c1)(O)R^(b1), NR^(c1)C(O)OR^(a1),        NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),        C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1), R^(d1),        S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),        OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1),        NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);    -   each R² is independently selected from halo, C₁₋₆ alkyl, CN,        OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and        S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl is optionally        substituted with 1, 2, or 3 substituents independently selected        from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),        C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5), C(O)R^(b5), NR^(c5)C(O)OR^(a5),        NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);    -   wherein each R² is substituted on any ring-forming atom of ring        B except the ring-forming atom of ring B to which R^(Z) is        bonded;    -   each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2), SR^(a2),        C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),        NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),        C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),        OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2), NR^(c2)C(O)R^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);    -   R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),        C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),        NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),        NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),        C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)²NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),        OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);    -   R⁵ and R⁶ are each independently selected from H, halo, CN, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, and —(C₁₋₄        alkyl)-OR^(a4);    -   R⁷ is H, C₁₋₄ alkyl or C₁₋₄ haloalkyl;    -   each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1),        R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), and        R^(d3) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1,        2, 3, 4, or 5 substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4),        SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)²R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c) and R^(d) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c1) and R^(d1) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c2) and R^(d2) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl, C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4),        C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),        OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),        NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said        C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-6 membered heteroaryl are optionally        substituted by 1, 2, or 3 substituents independently selected        from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,        OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c2) and R^(d3) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)OR^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   each R^(a4), R^(b4), R^(c4), and R^(d4) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   or any R^(c4) and R^(d4) together with the N atom to which they        are attached form a 3-, 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        substituents independently selected from OH, CN, amino, halo,        C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino,        di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is        independently selected from H, C₁₋₄ alkyl, and CN;    -   each WS, R^(a5), R^(b5), R^(c5), R^(d5) is independently        selected from H and C₁₋₆ alkyl optionally substituted with 1, 2,        3, 4, or 5 substituents independently selected from halo, CN,        OR^(a6), SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),        OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),        NR^(c6)(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),        C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),        S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),        NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);    -   each R^(a6), R^(b6), R^(c6), and R^(d6) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e6) is independently selected from H, C₁₋₄ alkyl, and        CN;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2;    -   wherein when ring B is 6-membered heterocycloalkyl, q is 0, and        L is S(O)₂, then ring C is other than thienyl.

In some embodiments, wherein when ring B is 5-6 memberedheterocycloalkyl, A is phenyl, q is 1 or 2, and R⁴ is halo, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 membered heteroaryl, CN,OR^(a3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)C(O)R^(b3),NR^(c3)S(O)₂R^(b3), or S(O)₂R^(b3), then R^(Z) is not H or C(O)OR^(a1).

In some embodiments, ring B is monocyclic 4-7 membered heterocycloalkylhaving carbon and 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, ring B is a 4-10 membered heterocycloalkyl havingcarbon and 1, 2, or 3 heteroatoms selected from N, O, and S wherein saidring B comprises at least one ring-forming N atom.

In some embodiments, ring B is a 4-7 membered heterocycloalkyl havingcarbon and 1, 2, or 3 heteroatoms selected from N, O, and S wherein saidring B comprises at least one ring-forming N atom.

In some embodiments, ring B is a 6-membered heterocycloalkyl ring havingcarbon and 1 or 2 heteroatoms selected from N, O, and S wherein saidring B comprises at least one ring-forming N atom.

In some embodiments, ring B is an azetidinyl or piperidinyl ring.

In some embodiments, ring B is an azetidinyl ring.

In some embodiments, ring B is a piperidine ring.

In some embodiments, ring C is bound to a ring-forming N atom of ring B.

In some embodiments, ring A is C₆₋₁₀ aryl or 5-10 membered heteroarylhaving carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring B is 4-10 membered heterocycloalkyl havingcarbon and 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, ring C is (1) C₆₋₁₀ aryl, (2) C₃₋₁₀ cycloalkyl, (3)5-10 membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatomsselected from N, O, and S, or (4) 4-20 membered heterocycloalkyl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, the compounds of the invention include a compoundof Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon        and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C is (1) C₆₋₁₀ aryl, (2) C₃₋₁₀ cycloalkyl, (3) 5-10        membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms        selected from N, O, and S, or (4) 4-20 membered heterocycloalkyl        having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O,        and S;    -   X is —CH₂— or —CH₂—CH₂—;    -   Y is —CH₂— or —CH₂—CH₂—;    -   L is C₁₋₄ alkylene, —C(═O)—, —C(═O)O—, —C(═O)NR⁷—, 0, NR′,        —S(O)₂—, —S(O)—, or —S(O)₂NR⁷—;    -   each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),        C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),        OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),        C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),        NR'S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d),        S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,        CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),        OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),        NR^(c)C(═NR^(e))NR^(c)R^(d), Nine, NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),        NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),        S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);    -   R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),        C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),        NR^(c1)R^(d1), NR^(c1)(O)R^(b1), NR^(c1)C(O)OR^(a1),        NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),        C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),        OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1),        NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);    -   each R² is independently selected from halo, C₁₋₆ alkyl, CN,        OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and        S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl is optionally        substituted with 1, 2, or 3 substituents independently selected        from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),        C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5), C(O)R^(b5), NR^(c5)C(O)OR^(a5),        NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);    -   wherein each R² is substituted any ring-forming carbon atom of        the ring in Formula II containing X and Y except the        ring-forming carbon atom to which R^(Z) is bonded;    -   each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2), SR^(a2),        C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),        NR^(c1)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),        C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),        OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);    -   R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),        C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),        NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),        NR^(c3)C(O)NR^(c3)R^(d3), (═NR^(e3))R^(b3),        C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)²NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),        OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);    -   R⁵ and R⁶ are each independently selected from H, halo, CN, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, and —(C₁₋₄        alkyl)-OR^(a4);    -   R⁷ is H or C₁₋₄ alkyl;    -   each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1),        R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), and        R^(d3) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1,        2, 3, 4, or 5 substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR″, SR^(a4),        (O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),        OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),        NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c) and R^(d) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(b4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c1) and R^(d1) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), (═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c2) and R^(d2) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl, C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4),        C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),        OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),        NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said        C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-6 membered heteroaryl are optionally        substituted by 1, 2, or 3 substituents independently selected        from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,        OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)_(OR)        ^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4); NR^(c4)C(═NR^(d4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c3) and R^(d3) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)OR^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   each R^(a4); R^(b4), R^(c4), and R^(d4) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   or any R^(c4) and R^(d4) together with the N atom to which they        are attached form a 3-, 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        substituents independently selected from OH, CN, amino, halo,        C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino,        di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; and    -   each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is        independently selected from H, C₁₋₄ alkyl, and CN;    -   each R^(a5), R^(b5), R^(c5), R^(d5) is independently selected        from H and C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or        5 substituents independently selected from halo, CN, OR^(a6),        SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),        OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),        NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),        C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),        S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),        NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);    -   each R^(a6), R^(b6), R^(c6), and R^(d6) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e6) is independently selected from H, C₁₋₄ alkyl, and        CN;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2;    -   wherein when X and Y are both —CH₂—CH₂—, q is 0, and L is S(O)₂,        then ring C is other than thienyl.

In some embodiments, wherein when one of X and Y is —CH₂—CH₂— and theother of X and Y is —CH₂—, A is phenyl, q is 1 or 2, and R⁴ is halo,C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 memberedheteroaryl, CN, OR^(a3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), or S(O)₂R^(b3), then R^(Z) is notH or C(O)OR^(a1).

In some embodiments, the compounds of the invention include a compoundof Formula IIIa or IIIb:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon        and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C is (1) C₆₋₁₀ aryl, (2) C₃₋₁₀ cycloalkyl, (3) 5-10        membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms        selected from N, O, and S, or (4) 4-20 membered heterocycloalkyl        having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O,        and S;    -   L is C₁₋₄ alkylene, —C(═O)—, —C(═O)O—, —C(═O)NR⁷—, O, NR⁷,        —S(O)₂—, —S(O)—, or —S(O)₂NR⁷—;    -   each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),        C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),        OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),        C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),        NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d),        S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,        CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),        OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),        NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),        NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),        S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);    -   R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),        C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),        NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),        NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),        C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),        OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1),        NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);    -   each R² is independently selected from halo, C₁₋₆ alkyl, CN,        OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and        S(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl is optionally        substituted with 1, 2, or 3 substituents independently selected        from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),        C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),        NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);    -   wherein each R² is substituted on any ring-forming carbon atom        of the azetidine ring depicted in Formula IIIa or the piperidine        ring depicted in Formula IIIb except the ring-forming carbon        atom to which R^(Z) is bonded;    -   each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2), SR^(a2),        C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),        NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),        C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),        OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);    -   R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),        C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),        NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),        NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),        C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),        OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); R⁵ and R⁶ are each        independently selected from H, halo, CN, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ cyanoalkyl, and —(C₁₋₄ alkyl)-OR^(a4); R⁷ is H        or C₁₋₄ alkyl;    -   each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1),        R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), and        R^(d3) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1,        2, 3, 4, or 5 substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4),        SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c) and R^(d) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c1) and R^(d1) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c2) and R^(d2) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl, C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4),        C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),        OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),        NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said        C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-6 membered heteroaryl are optionally        substituted by 1, 2, or 3 substituents independently selected        from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,        OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c3) and R^(d3) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   each R^(a4), R^(b4), R^(c4), and R^(d4) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   or any R^(c4) and R^(d4) together with the N atom to which they        are attached form a 3-, 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        substituents independently selected from OH, CN, amino, halo,        C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino,        di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is        independently selected from H, C₁₋₄ alkyl, and CN;    -   each R^(a5), R^(b5), R^(c5), R^(d5) is independently selected        from H and C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or        5 substituents independently selected from halo, CN, OR^(a6),        SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),        OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),        NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),        C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),        S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),        NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);    -   each R^(a6), R^(b6), R^(c6), and R^(d6) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e6) is independently selected from H, C₁₋₄ alkyl, and        CN;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2;    -   wherein in Formula IIIb when q is 0 and L is S(O)₂, then ring C        is other than thienyl.

In some embodiments, in Formula IIIb when A is phenyl, q is 1 or 2, andR⁴ is halo, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10membered heteroaryl, CN, OR^(a3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), or S(O)₂R^(b3), then R^(Z) is notH or C(O)OR^(a1).

In some embodiments, the compounds of the invention have Formula IIIa:

In some embodiments, the compounds of the invention have Formula IIIb:

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, ring A is phenyl.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, each R¹ is independently selected from halo and—O—(C₁₋₆ alkyl).

In some embodiments, each R¹ is independently selected from F andmethoxy.

In some embodiments, both R⁵ and R⁶ are H.

In some embodiments, R⁵ and R⁶ are each independently selected from Hand C₁₋₄ alkyl.

In some embodiments, R⁵ is H and R⁶ is methyl.

In some embodiments, L is —(CH₂)_(r)—, —C(═O)—, —C(═O)O—, —C(═O)NR⁷—, or—S(O)₂—, wherein r is 1, 2, 3, or 4.

In some embodiments, L is —CH₂—, —C(═O)—, —C(═O)O—, —C(═O)NH—, or—S(O)₂—.

In some embodiments, L is —(CH₂)_(r)—, —C(═O)—, —C(═O)NR⁷—, or —S(O)₂—,wherein r is 1, 2, 3, or 4.

In some embodiments, L is —CH₂—, —C(═O)—, —C(═O)NH—, or —S(O)₂—.

In some embodiments, L is —CH₂—.

In some embodiments, L is —C(═O)—.

In some embodiments, L is —S(O)₂—.

In some embodiments, ring C is phenyl.

In some embodiments, ring C is monocyclic C₃₋₇ cycloalkyl.

In some embodiments, ring C is cyclopentyl.

In some embodiments, ring C is cyclobutyl.

In some embodiments, ring C is cyclopropyl.

In some embodiments, ring C is monocyclic 5- or 6-membered heteroarylhaving carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring C is monocyclic 6-membered heteroaryl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring C is 4-20 membered heterocycloalkyl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring C is 4-7 membered heterocycloalkyl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring C is 5-6 membered heterocycloalkyl havingcarbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

In some embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, imidazolyl, pyridazinyl, pyrazolyl, pyrimidinyl, phenyl,pyridyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl,

In some embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, imidazolyl, pyridazinyl, pyrazolyl, pyrimidinyl, phenyl,pyridyl, piperidinyl, tetrahydrofuranyl,

In some embodiments, ring C is phenyl, pyridyl, piperidinyl,tetrahydrofuranyl,

In some embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, imidazolyl, pyridazinyl, pyrazolyl, pyrimidinyl, phenyl,piperidinyl, pyrrolidinyl, azetidinyl,

In some embodiments, ring C is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, imidazolyl, pyridazinyl, pyrazolyl, pyrimidinyl, phenyl,piperidinyl,

In some embodiments, R⁴ is C₁₋₆ alkyl, halo, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, CN, OR^(a3), NR^(c3)R^(d3), or C(O)OR^(a3), whereinsaid C₁₋₆ alkyl, C₆₋₁₀ aryl, and C₃₋₁₀ cycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, R⁴ is halo, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, CN, OR^(a3), or C(O)OR^(a3), wherein said C₆₋₁₀ aryl andC₃₋₁₀ cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3).

In some embodiments, R⁴ is F, CF₃, phenyl, cyclohexyl substituted byhydroxyl, CN, OCH₃, OCF₃, or COOH.

In some embodiments, R⁴ is C(O)OR^(a3).

In some embodiments, each R³ is independently selected from halo, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, CN, OR^(a2), and C(O)OR^(a2),wherein said C₆₋₁₀ aryl and C₃₋₁₀ cycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, R^(Z) is H, C₁₋₄ alkyl, or C₆₋₁₀ aryl-C₁₋₄ alkyl-,or (5-10 membered heteroaryl)-C₁₋₄ alkyl-, wherein said C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl- and (5-10 membered heteroaryl)-C₁₋₄ alkyl- areeach optionally substituted by CN, halo, OR^(a1), C(O)OR^(a1), or C₁₋₄cyanoalkyl.

In some embodiments, R^(Z) is H, C₁₋₄ alkyl, or C₆₋₁₀ aryl-C₁₋₄ alkyl-,wherein said C₁₋₄ alkyl and C₆₋₁₀ aryl-C₁₋₄ alkyl- are each optionallysubstituted by CN, halo, OR^(a1), or C₁₋₄ cyanoalkyl.

In some embodiments, R^(Z) is C₁₋₄ alkyl.

In some embodiments, R^(Z) is C₆₋₁₀ aryl-C₁₋₄ alkyl-substituted byfluoro or cyanomethyl.

In some embodiments, R^(Z) is C₁₋₄ alkyl substituted by methoxy or CN.

In some embodiments, R^(Z) is (5-10 membered heteroaryl)-C₁₋₄alkyl-substituted by methoxy or F.

In some embodiments, R^(Z) is H, methyl, cyanomethyl, methoxymethyl,4-fluorophenylmethyl or 4-(cyanomethyl)phenylmethyl.

In some embodiments, R^(Z) is H, methyl, cyanomethyl, methoxymethyl,ethoxymethyl, 4-fluorophenylmethyl, 3-cyanophenylmethyl,4-cyanophenylmethyl, 3-carboxyphenylmethyl,6-methoxypyridin-3-yl)methyl, 4-cyano-2-fluorobenzyl, (benzyloxy)methyl,(cyclobutylmethoxy)methyl, (cyclohexyloxy)methyl,(5-fluoropyridin-2-yl)methyl, 4-methoxyphenylmethyl,(2-fluorophenoxy)methyl, (3-fluorophenoxy)methyl,(2-cyanophenoxy)methyl, (3-cyanophenoxy)methyl, (4-cyanophenoxy)methyl,(4-cyano-2-fluorophenoxy)methyl, (5-fluoropyridin-2-yl)oxymethyl,(5-fluoropyrimidin-2-yl)oxymethyl, (3-fluoropyridin-2-yl)oxymethyl,(6-(methylaminocarbonyl)pyridin-3-yl)oxymethyl,(6-(methylaminocarbonyl)pyridin-2-yl)oxymethyl, or4-(cyanomethyl)phenylmethyl.

In some embodiments, R^(Z) is H or C₁₋₄ alkyl substituted by CN.

In some embodiments, R^(Z) is cyanomethyl.

In some embodiments, R^(Z) is methoxymethyl.

In some embodiments, R^(Z) is H.

In some embodiments, R^(Z) is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1).

In some embodiments, m is 0.

In some embodiments, the compound of the invention is a compound FormulaIIIa:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon        and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C is (1) C₆₋₁₀ aryl, (2) C₃₋₁₀ cycloalkyl, (3) 5-10        membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms        selected from N, O, and S, or (4) 4-20 membered heterocycloalkyl        having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O,        and S;    -   L is C₁₋₄ alkylene, —C(═O)—, —C(═O)O—, —C(═O)NR⁷—, O, NR⁷,        —S(O)₂—, —S(O)—, or —S(O)₂NR⁷—;    -   each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),        C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),        OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),        C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),        NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d),        S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,        CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),        OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),        NR^(c)C(═NR^(e)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),        NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),        S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);    -   R^(Z) is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),        C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),        NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),        NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),        C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),        OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1),        NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1) NR^(c1)C(O)NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);    -   each R² is independently selected from halo, C₁₋₆ alkyl, CN,        OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and        S(O)₂NR^(c)R^(d5), wherein said C₁₋₆ alkyl is optionally        substituted with 1, 2, or 3 substituents independently selected        from halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),        C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e))NR^(c5)R^(d5),        NR^(c)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),        NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b),        NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);    -   wherein each R² is substituted on any ring-forming carbon atom        of the azetidine ring depicted in Formula IIIa or the piperidine        ring depicted in Formula IIIb except the ring-forming carbon        atom to which R^(Z) is bonded;    -   each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2), SR^(a2),        C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),        NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),        C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),        OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);    -   R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),        C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),        NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),        NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),        C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),        OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);    -   R⁵ and R⁶ are each independently selected from H, halo, CN, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, and —(C₁₋₄        alkyl)-OR^(a4); R⁷ is H or C₁₋₄ alkyl;    -   each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1),        R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), and        R^(d3) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1,        2, 3, 4, or 5 substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4),        SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c) and R^(d) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c1) and R^(d1) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c2) and R^(d2) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl, C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4),        C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),        OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),        NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said        C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-6 membered heteroaryl are optionally        substituted by 1, 2, or 3 substituents independently selected        from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,        OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c3) and R^(d3) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   each R^(a4), R^(b4), R^(c4), and R^(d4) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   or any R^(c4) and R^(d4) together with the N atom to which they        are attached form a 3-, 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        substituents independently selected from OH, CN, amino, halo,        C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino,        di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is        independently selected from H, C₁₋₄ alkyl, and CN;    -   each R^(a5), R^(b5), R^(c5), R^(d5) is independently selected        from H and C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or        5 substituents independently selected from halo, CN, OR^(a6),        SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),        OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),        NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),        C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),        S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),        NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);    -   each R^(a6), R^(b6), R^(c6), and R^(d6) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e6) is independently selected from H, C₁₋₄ alkyl, and        CN;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2.

In some embodiments, wherein the compounds have Formula IIIa, q is 1.

In some embodiments, wherein the compounds have Formula IIIa, ring A isphenyl.

In some embodiments, wherein the compounds have Formula IIIa, n is 0.

In some embodiments, wherein the compounds have Formula IIIa, both R⁵and R⁶ are H.

In some embodiments, wherein the compounds have Formula IIIa, L is—CH₂—, —C(═O)—, —C(═O)NH—, or —S(O)₂—.

In some embodiments, wherein the compounds have Formula IIIa, ring C isphenyl.

In some embodiments, wherein the compounds have Formula IIIa, ring C is4-20 membered heterocycloalkyl having carbon and 1, 2, 3 or 4heteroatoms selected from N, O, and S.

In some embodiments, wherein the compounds have Formula IIIa, ring C isphenyl, piperidinyl,

In some embodiments, wherein the compounds have Formula IIIa, ring C isphenyl.

In some embodiments, wherein the compounds have Formula IIIa, R⁴ is C₁₋₆alkyl, halo, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, CN, OR^(a3),NR^(c3)R^(d3), or C(O)OR^(a3), wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, andC₃₋₁₀ cycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3).

In some embodiments, wherein the compounds have Formula IIIa, R⁴ ishalo, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, CN, OR^(a3), orC(O)OR^(a3), wherein said C₆₋₁₀ aryl and C₃₋₁₀ cycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3).

In some embodiments, wherein the compounds have Formula IIIa, p is 0.

In some embodiments, wherein the compounds have Formula IIIa, p is 1.

In some embodiments, wherein the compounds have Formula IIIa, R^(Z) isH, C₁₋₄ alkyl, or C₆₋₁₀ aryl-C₁₋₄ alkyl-, wherein said C₁₋₄ alkyl andC₆₋₁₀ aryl-C₁₋₄ alkyl- are each optionally substituted by CN, halo,OR^(a1), or C₁₋₄ cyanoalkyl.

In some embodiments, wherein the compounds have Formula IIIa, R^(Z) isH.

In some embodiments, wherein the compounds have Formula IIIa, m is 0.

In some embodiments, the compound of the invention is a compound ofFormula IIIb:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is C₆₋₁₀ aryl or 5-10 membered heteroaryl having carbon        and 1, 2, 3 or 4 heteroatoms selected from N, O, and S;    -   ring C is (1) C₆₋₁₀ aryl, (2) C₃₋₁₀ cycloalkyl, (3) 5-10        membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms        selected from N, O, and S, or (4) 4-20 membered heterocycloalkyl        having carbon and 1, 2, 3 or 4 heteroatoms selected from N, O,        and S; L is C₁₋₄ alkylene, —C(═O)—, —C(═O)O—, —C(═O)NR⁷—, O,        NR⁷, —S(O)₂—, —S(O)—, or —S(O)₂NR⁷—;    -   each R¹ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆-1 aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),        C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),        OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),        C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),        NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d),        S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl,        CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),        OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),        NR^(c)C(═NR^(e)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),        NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),        S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d);    -   R^(Z) is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),        C(O)NR^(c1)R^(d1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),        NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),        NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),        C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),        OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),        NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1),        NR^(c1)C(O)R^(b1), NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);    -   each R² is independently selected from halo, C₁₋₆ alkyl, CN,        OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and        S(O)₂NR^(c)R^(d5),    -   wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or        3 substituents independently selected from halo, CN, OR^(a5),        SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)C(═NR^(e))NR^(c5)R^(d5), NR^(c)R^(d5), NR^(c5)C(O)R^(b5),        NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b),        NR^(c5)S(O)₂R^(b), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),        S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);    -   wherein each R² is substituted on any ring-forming carbon atom        of the azetidine ring depicted in Formula IIIa or the piperidine        ring depicted in Formula IIIb except the ring-forming carbon        atom to which R^(Z) is bonded;    -   each R³ is independently selected from halo, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2), SR^(a2),        C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),        NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),        C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),        OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),        NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2),        NR^(c2)C(O)R^(b2) NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);    -   R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),        C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),        NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),        NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),        C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂,        OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),        OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3),        NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);    -   R⁵ and R⁶ are each independently selected from H, halo, CN, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, and —(C₁₋₄        alkyl)-OR^(a4);    -   R⁷ is H or C₁₋₄ alkyl;    -   each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1),        R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), and        R^(d3) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1,        2, 3, 4, or 5 substituents independently selected from C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4),        SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c) and R^(d) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c1) and R^(d1) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   or any R^(c2) and R^(d2) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl, C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4),        C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),        OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),        NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said        C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-6 membered heteroaryl are optionally        substituted by 1, 2, or 3 substituents independently selected        from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,        OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),        OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),        NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),        C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),        S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),        NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4);    -   or any R^(c3) and R^(d3) together with the N atom to which they        are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl        group optionally substituted with 1, 2, or 3 substituents        independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,        4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered        heteroaryl are optionally substituted by 1, 2, or 3 substituents        independently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),        C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),        NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),        NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),        NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),        S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4);    -   each R^(a4), R^(b4), R^(c4), and R^(d4) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   or any R^(c4) and R^(d4) together with the N atom to which they        are attached form a 3-, 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        substituents independently selected from OH, CN, amino, halo,        C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino,        di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is        independently selected from H, C₁₋₄ alkyl, and CN;    -   each R^(a5), R^(b5), R^(c5), R^(d5) is independently selected        from H and C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4, or        5 substituents independently selected from halo, CN, OR^(a6),        SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6),        OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),        NR^(c6)C(O)R^(b6), NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6),        C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),        S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6),        NR^(c6)S(O)₂NR^(c6)R^(d6), and S(O)₂NR^(c6)R^(d6);    -   each R^(a6), R^(b6), R^(c6), and R^(d6) is independently        selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and        C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, is optionally substituted with 1, 2, or 3 substituents        independently selected from OH, CN, amino, halo, C₁₋₄ alkyl,        C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄        alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;    -   each R^(e6) is independently selected from H, C₁₋₄ alkyl, and        CN;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, or 2;    -   wherein in Formula IIIb when q is 0 and L is S(O)₂, then ring C        is other than thienyl.

In some embodiments, wherein the compound has Formula IIIb, q is 1.

In some embodiments, wherein the compound has Formula IIIb, ring A isphenyl.

In some embodiments, wherein the compound has Formula IIIb, n is 0.

In some embodiments, wherein the compound has Formula IIIb, n is 1.

In some embodiments, wherein the compound has Formula IIIb, n is 2.

In some embodiments, wherein the compound has Formula IIIb, each R¹ isindependently selected from halo and —O—(C₁₋₆ alkyl).

In some embodiments, wherein the compound has Formula IIIb, each R¹ isindependently selected from F and methoxy.

In some embodiments, wherein the compound has Formula IIIb, both R⁵ andR⁶ are H.

In some embodiments, wherein the compound has Formula IIIb, R⁵ and R⁶are each independently selected from H and C₁₋₄ alkyl.

In some embodiments, wherein the compound has Formula IIIb, R⁵ is H andR⁶ is methyl.

In some embodiments, wherein the compound has Formula IIIb, L is —CH₂—.

In some embodiments, wherein the compound has Formula IIIb, L is—C(═O)—.

In some embodiments, wherein the compound has Formula IIIb, L is—S(O)₂—.

In some embodiments, wherein the compound has Formula IIIb, ring C isphenyl.

In some embodiments, wherein the compound has Formula IIIb, ring C ismonocyclic C₃₋₇ cycloalkyl.

In some embodiments, wherein the compound has Formula IIIb, ring C iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, wherein the compound has Formula IIIb, ring C ismonocyclic 5- or 6-membered heteroaryl having carbon and 1, 2, 3 or 4heteroatoms selected from N, O, and S.

In some embodiments, wherein the compound has Formula IIIb, ring C ispyrazolyl, imidazolyl, pyrimidinyl, or pyridazinyl.

In some embodiments, wherein the compound has Formula IIIb, ring C is4-6 membered heterocycloalkyl having carbon and 1, 2, 3 or 4 heteroatomsselected from N, O, and S.

In some embodiments, wherein the compound has Formula IIIb, ring C ispiperidinyl, pyrolidinyl, azetidinyl, or piperazinyl.

In some embodiments, wherein the compound has Formula IIIb, ring C ispiperidinyl, pyrolidinyl, or piperazinyl.

In some embodiments, wherein the compound has Formula IIIb, R⁴ is C₁₋₆alkyl, halo, NR^(c3)R^(d3), C(O)OR^(a3), CN, —(C₁₋₆ alkyl)-CN, —OR^(a3),or —(C₁₋₆ alkyl)-OR^(a3).

In some embodiments, wherein the compound has Formula IIIb, R⁴ is C₁₋₆alkyl, halo, NR^(c3)R^(d3), or C(O)OR^(a3).

In some embodiments, wherein the compound has Formula IIIb, R⁴ isC(O)OR^(a3).

In some embodiments, wherein the compound has Formula IIIb, p is 0.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) isC₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, or C₆₋₁₀ aryl-C₁₋₄alkyl-, wherein said C₁₋₄ alkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and C₆₋₁₀ aryl-C₁₋₄ alkyl- are each optionally substituted by CN, halo,OR^(a1), C(O)OR^(a1), or C₁₋₄ cyanoalkyl.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) isC₁₋₄ alkyl or C₆₋₁₀ aryl-C₁₋₄ alkyl-, wherein said C₁₋₄ alkyl and C₆₋₁₀aryl-C₁₋₄ alkyl- are each optionally substituted by CN, halo, OR^(a1),or C₁₋₄ cyanoalkyl.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) isC₁₋₄ alkyl.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) isC₆₋₁₀ aryl-C₁₋₄ alkyl-substituted by fluoro or cyanomethyl.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) isC₁₋₄ alkyl substituted by methoxy or CN.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) is(5-10 membered heteroaryl)-C₁₋₄ alkyl-substituted by methoxy or F.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) ismethyl, cyanomethyl, methoxymethyl, 4-fluorophenylmethyl or4-(cyanomethyl)phenylmethyl.

In some embodiments, wherein the compound has Formula IIIb, R^(Z) ismethyl, cyanomethyl, methoxymethyl, ethoxymethyl, 4-fluorophenylmethyl,3-cyanophenylmethyl, 4-cyanophenylmethyl, 3-carboxyphenylmethyl,6-methoxypyridin-3-yl)methyl, 4-cyano-2-fluorobenzyl, (benzyloxy)methyl,(cyclobutylmethoxy)methyl, (cyclohexyloxy)methyl,(5-fluoropyridin-2-yl)methyl, 4-methoxyphenylmethyl,(2-fluorophenoxy)methyl, (3-fluorophenoxy)methyl,(2-cyanophenoxy)methyl, (3-cyanophenoxy)methyl, (4-cyanophenoxy)methyl,(4-cyano-2-fluorophenoxy)methyl, (5-fluoropyridin-2-yl)oxymethyl,(5-fluoropyrimidin-2-yl)oxymethyl, (3-fluoropyridin-2-yl)oxymethyl,(6-(methylaminocarbonyl)pyridin-3-yl)oxymethyl,(6-(methylaminocarbonyl)pyridin-2-yl)oxymethyl, or4-(cyanomethyl)phenylmethyl.

In some embodiments, wherein the compound has Formula IIIb, m is 0.

In some embodiments, the compound has a trans configuration with respectto the di-substituted cyclopropyl group depicted in Formula I (or any ofFormulas II, IIIa, and IIIb).

In some embodiments of compounds of Formulas I, II, IIIa, or IIIb, thestereoconfiguration of the carbon atom on the cyclopropyl groupconnected to Ring A is R and the stereoconfiguration of the carbon atomon the cyclopropyl group connected to NH linkage is S.

In some embodiments of compounds of Formulas I, II, IIIa, or IIIb, thestereoconfiguration of the carbon atom on the cyclopropyl groupconnected to Ring A is S and the stereoconfiguration of the carbon atomon the cyclopropyl group connected to NH linkage is R.

In some embodiments of compounds of Formulas I, II, IIIa, or IIIb, thestereoconfiguration of the carbon atom on the cyclopropyl groupconnected to Ring A is R and the stereoconfiguration of the carbon atomon the cyclopropyl group connected to NH linkage is R.

In some embodiments of compounds of Formulas I, II, IIIa, or IIIb, thestereoconfiguration of the carbon atom on the cyclopropyl groupconnected to Ring A is S and the stereoconfiguration of the carbon atomon the cyclopropyl group connected to NH linkage is S.

In some embodiments, each R^(a), R^(b), R^(c), and R^(d) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4).

In some embodiments, each R^(a1), R^(b1), R^(c1), and R^(d1) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4).

In some embodiments, each R^(a3), R^(b3), R^(c3), and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4).

In some embodiments, each R^(a), R^(b), R^(c), and R^(d) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.

In some embodiments, each R^(a1), R^(b1), R^(c1), and R^(d1) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.

In some embodiments, each R^(a3), R^(b3), R^(c3), and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.

In some embodiments, each R^(a), R^(b), R^(c), and R^(d) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a1), R^(b1), R^(c1), and R^(d1) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a3), R^(b3), R^(c3), and R^(d3) isindependently selected from H and C₁₋₆ alkyl.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

A floating bond crossing a ring moiety in any structure or formuladepicted herein is intended to show, unless otherwise indicated, thatthe bond can connect to any ring-forming atom of the ring moiety. Forexample, where ring A in Formula I is a naphthyl group, an R¹substituent, if present, can be substituted on either of the two ringsforming the naphthyl group.

In regard to linking group L, the groups listed as choices for L are notintended to have directionality. For example, when L is —C(═O)NR⁷—, itis meant to include both —C(═O)NR⁷— and —NR⁷C(═O)—.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_(i-j)” indicates a range whichincludes the endpoints, wherein i and j are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “z-membered” (where z is an integer) typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is z. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example ofa 10-membered cycloalkyl group.

The term “carbon” refers to one or more carbon atoms.

As used herein, the term “C_(i-j) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having i to j carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, refers to a saturated linking (e.g.,divalent) hydrocarbon group that may be straight-chain or branched,having i to j carbons. In some embodiments, the alkylene group containsfrom 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2carbon atoms. Examples of alkyl moieties include, but are not limitedto, chemical groups such as methylene, ethylene, 1,1-ethylene,1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene,and the like.

As used herein, the term “C_(i-j) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has i to j carbons. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, “C_(i-j) alkenyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore double carbon-carbon bonds and having i to j carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(i-j) alkynyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore triple carbon-carbon bonds and having i to j carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_(i-j) alkylamino,” employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has i to j carbon atoms.

In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.Exemplary alkylamino groups include methylamino, ethylamino, and thelike.

As used herein, the term “di-C_(i-j)-alkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein each of the two alkyl groups has, independently, i to j carbonatoms. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms. In some embodiments, the dialkylamino group is—N(C₁₋₄ alkyl)₂ such as, for example, dimethylamino or diethylamino.

As used herein, the term “C_(i-j) alkylthio,” employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylthio group is C₁₋₄ alkylthio such as, for example, methylthioor ethylthio.

As used herein, the term “amino,” employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl is C₆₋₁₀aryl. In some embodiments, the aryl group is a naphthalene ring orphenyl ring. In some embodiments, the aryl group is phenyl.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(i-j) cyanoalkyl,” employed alone or incombination with other terms, refers to an alkyl group substituted by aCN group.

As used herein, the term “C_(i-j) cycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, which mayoptionally contain one or more alkenylene groups as part of the ringstructure. Cycloalkyl groups can include mono- or polycyclic (e.g.,having 2, 3 or 4 fused rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl, or C₅₋₆cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. Further exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, “C_(i-j) haloalkoxy,” employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl having i toj carbon atoms. An example haloalkoxy group is OCF₃. An additionalexample haloalkoxy group is OCHF₂. In some embodiments, the haloalkoxygroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group isC₁₋₄ haloalkoxy.

As used herein, the term “halo,” employed alone or in combination withother terms, refers to a halogen atom selected from F, Cl, I or Br. Insome embodiments, “halo” refers to a halogen atom selected from F, Cl,or Br. In some embodiments, the halo substituent is F.

As used herein, the term “C_(i-j) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has i to j carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic heterocylic moiety, having one or moreheteroatom ring members selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ringmembers. In some embodiments, the heteroaryl group has 1, 2, or 3heteroatom ring members. In some embodiments, the heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the heteroaryl grouphas 1 heteroatom ring member. In some embodiments, the heteroaryl groupis 5- to 10-membered or 5- to 6-membered. In some embodiments, theheteroaryl group is 5-membered. In some embodiments, the heteroarylgroup is 6-membered. In some embodiments, the heteroaryl ring has orcomprises carbon and 1, 2, 3 or 4 heteroatoms selected from N, O, and S.When the heteroaryl group contains more than one heteroatom ring member,the heteroatoms may be the same or different. The nitrogen atoms in thering(s) of the heteroaryl group can be oxidized to form N-oxides.Example heteroaryl groups include, but are not limited to, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl,thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl,isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1, 2-b]thiazolyl, purinyl, triazinyl, and the like.

A 5-membered heteroaryl is a heteroaryl group having five ring-formingatoms wherein one or more of the ring-forming atoms are independentlyselected from N, O, and S. In some embodiments, the 5-memberedheteroaryl group has 1, 2, or 3 heteroatom ring members. In someembodiments, the 5-membered heteroaryl group has 1 or 2 heteroatom ringmembers. In some embodiments, the 5-membered heteroaryl group has 1heteroatom ring member. Example ring-forming members include CH, N, NH,O, and S. Example five-membered ring heteroaryls are thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2,3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2,4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3,4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring-formingatoms wherein one or more of the ring-forming atoms is N. In someembodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatomring members. In some embodiments, the 6-membered heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the 6-memberedheteroaryl group has 1 heteroatom ring member. Example ring-formingmembers include CH and N. Example six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to non-aromatic heterocyclic ringsystem, which may optionally contain one or more unsaturations as partof the ring structure, and which has at least one heteroatom ring memberindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatomring members. In some embodiments, the heterocycloalkyl group has 1, 2,or 3 heteroatom ring members. In some embodiments, the heterocycloalkylgroup has 1 or 2 heteroatom ring members. In some embodiments, theheterocycloalkyl group has 1 heteroatom ring member. In someembodiments, the heterocycloalkyl group has or comprises carbon and 1,2, or 3 heteroatoms selected from N, O, and S. When the heterocycloalkylgroup contains more than one heteroatom in the ring, the heteroatoms maybe the same or different. Example ring-forming members include CH, CH₂,C(O), N, NH, O, S, S(O), and S(O)₂. Heterocycloalkyl groups can includemono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems,including spiro systems. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the non-aromatic ring, forexample, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and thelike. The carbon atoms or heteroatoms in the ring(s) of theheterocycloalkyl group can be oxidized to form a carbonyl, sulfinyl, orsulfonyl group (or other oxidized linkage) or a nitrogen atom can bequaternized. In some embodiments, heterocycloalkyl is 5- to 10-membered,4- to 10-membered, 4- to 7-membered, 5-membered, or 6-membered. Examplesof heterocycloalkyl groups include 1, 2, 3, 4-tetrahydro-quinolinyl,dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compounds with asingle chiral center, the stereochemistry of the chiral center can be(R) or (S). In compounds with two chiral centers, the stereochemistry ofthe chiral centers can each be independently (R) or (S) so theconfiguration of the chiral centers can be (R) and (R), (R) and (S); (S)and (R), or (S) and (S). In compounds with three chiral centers, thestereochemistry each of the three chiral centers can each beindependently (R) or (S) so the configuration of the chiral centers canbe (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and(S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S)and (S).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid.

Other resolving agents suitable for fractional crystallization methodsinclude stereoisomerically pure forms of α-methylbenzylamine (e.g., Sand R forms, or diastereoisomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified (e.g., in the case of purine rings,unless otherwise indicated, when the compound name or structure has the9H tautomer, it is understood that the 7H tautomer is also encompassed).

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in a compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD(N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N, N-diisopropylethylamine); DMF (N, N-dimethylformamide); EA(ethyl acetate); Et (ethyl); EtOAc (ethyl acetate); g (gram(s)); h(hour(s)); HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MS (Mass spectrometry); Me (methyl); MeCN(acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s));mL (milliliter(s)); mmol (millimole(s)); N (normal); nM (nanomolar); NMP(N-methylpyrrolidinone); NMR (nuclear magnetic resonance spectroscopy);OTf (trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); s (singlet); t(triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary);tt (triplet of triplets); TFA (trifluoroacetic acid); THF(tetrahydrofuran); tg (microgram(s)); tL (microliter(s)); μM(micromolar); wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006), which is incorporated herein by referencein its entirety. Protecting groups in the synthetic schemes aretypically represented by “PG.”

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of formula 3 can be prepared by the methods outlined inScheme 1. Reductive amination of compounds of formula 1 and aldehydes offormula 2 in a suitable solvent such as DCM using a reducing agent suchas, but not limited to, sodium triacetoxyborohydride, optionally in thepresence of an acid such as acetic acid, can give compounds of formula3. If any functional groups in compound 1 or 2 are protected to avoidany side reactions, a subsequent deprotection step can be performed toobtain the final product of formula 3. The deprotection conditions canbe found in the literature or detailed in the specific examplesdescribed below. The starting materials of formula 1 or 2 are eithercommercially available, or can be prepared as described herein, orprepared following methods disclosed in the literature.

Alternatively compounds of formula 3a can be prepared using methods asoutlined in Scheme 2 starting from aldehydes of formula 4, which arecommercially available or can be prepared as described in the literatureor herein. Reductive amination of cyclopropylamine derivatives offormula 1 with aldehyde 4 using similar conditions as described inScheme 1 can generate compounds of formula 5. The free amine group incompound 5 can then be protected with a suitable protecting group suchas trifluoroacetyl (CF₃CO), Cbz or allyloxycarbonyl (Alloc), followed byselective removal of the Boc protecting group with acid can givecompounds of formula 6. Displacement of the leaving group Lv (Lv is Cl,OMs, etc) in compounds of formula 7 by piperidine in compound 6 in thepresence of a suitable base such as DIEA can generate compounds offormula 8, which can be deprotected to afford the compounds of formula3a.

Compounds of formula 3b can be prepared by the method outlined in Scheme3 starting from compounds of formula 1 and formula 9 by reductiveamination in a suitable solvent such as DCM or THF using a reducingagent such as, but not limited to, sodium triacetoxyborohydride,optionally in the presence of an acid such as acetic acid. If anyfunctional groups in compound 1 or 9 are protected to avoid any sidereactions, a subsequent deprotection step can be performed to obtain thefinal product of formula 3b.

Cyclopropylamine derivatives of formula 1 can be prepared using methodsas outlined in Scheme 4, starting from the acrylate derivatives offormula 10 (R is alkyl such as ethyl) which are either commerciallyavailable or prepared using methods herein or in the literature.Cyclopropanation of compound 10 under standard conditions such as theCorey-Chaykovsky reaction can give the cyclopropyl derivatives offormula 11. The ester can be saponified to give acids of formula 12,which can be subjected to standard Curtius rearrangement conditionsfollowed by deprotection to give cyclopropylamine derivatives of formula1.

Methods of Use

Compounds of the invention are LSD1 inhibitors and, thus, are useful intreating diseases and disorders associated with activity of LSD1. Forthe uses described herein, any of the compounds of the invention,including any of the embodiments thereof, may be used.

In some embodiments, the compounds of the invention are selective forLSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 withgreater affinity or potency, compared to LSD2. In general, selectivitycan be at least about 5-fold, at least about 10-fold, at least about20-fold, at least about 50-fold, at least about 100-fold, at least about200-fold, at least about 500-fold or at least about 1000-fold.

As inhibitors of LSD1, the compounds of the invention are useful intreating LSD1-mediated diseases and disorders. The term “LSD1-mediateddisease” or “LSD1-mediated disorder” refers to any disease or conditionin which LSD1 plays a role, or where the disease or condition isassociated with expression or activity of LSD1. The compounds of theinvention can therefore be used to treat or lessen the severity ofdiseases and conditions where LSD1 is known to play a role.

Diseases and conditions treatable using the compounds of the inventioninclude generally cancers, inflammation, autoimmune diseases, viralinduced pathogenesis, beta-globinopathies, and other diseases linked toLSD1 activity.

Cancers treatable using compounds according to the present inventioninclude, for example, hematological cancers, sarcomas, lung cancers,gastrointestinal cancers, genitourinary tract cancers, liver cancers,bone cancers, nervous system cancers, gynecological cancers, and skincancers.

Example hematological cancers include, for example, lymphomas andleukemias such as acute lymphoblastic leukemia (ALL), acute myelogenousleukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-celllymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (includingrelapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), and multiple myeloma.

Example sarcomas include, for example, chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

Example lung cancers include, for example, non-small cell lung cancer(NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated smallcell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, andmesothelioma.

Example gastrointestinal cancers include, for example, cancers of theesophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoidtumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Example genitourinary tract cancers include, for example, cancers of thekidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder andurethra (squamous cell carcinoma, transitional cell carcinoma,adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma).

Example liver cancers include, for example, hepatoma (hepatocellularcarcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma,hepatocellular adenoma, and hemangioma.

Example bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Example nervous system cancers include, for example, cancers of theskull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans),meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), aswell as neuroblastoma and Lhermitte-Duclos disease.

Example gynecological cancers include, for example, cancers of theuterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Example skin cancers include, for example, melanoma, basal cellcarcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplasticnevi, lipoma, angioma, dermatofibroma, and keloids.

The compounds of the invention can further be used to treat cancer typeswhere LSD1 may be overexpressed including, for example, breast,prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g.,papillary thyroid carcinoma).

The compounds of the invention can further be used to treat geneticdisorders such as Cowden syndrome and Bannayan-Zonana syndrome.

The compounds of the invention can further be used to treat viraldiseases such as herpes simplex virus (HSV), varicella zoster virus(VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.

The compounds of the invention can further be used to treatbeta-globinopathies including, for example, beta-thalassemia and sicklecell anemia.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a LSD1 protein with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having a LSD1 protein, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the LSD1protein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease.

Combination Therapies

The compounds of the invention can be used in combination treatmentswhere the compound of the invention is administered in conjunction withother treatments such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3Kinhibitors for treatment of LSD1-mediated diseases, disorders orconditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. Histone deacetylase inhibitors include, e.g.,vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,or other anti-proliferative agents. The compounds of the invention canalso be used in combination with medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin,bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,panobinostat, pegaspargase, pegfilgrastim, pemetrexed disodium,pentostatin, pipobroman, plicamycin, procarbazine, quinacrine,rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib,sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone,thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine,vincristine, vinorelbine, vorinostat, and zoledronate.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with ruxolitinib.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, JAKl-selective), Pimkinase inhibitors, PI3 kinase inhibitors including PI3K-delta selectiveand broad spectrum PI3K inhibitors, MEK inhibitors, Cyclin Dependentkinase inhibitors, b-RAF inhibitors, mTOR inhibitors, Proteasomeinhibitors (Bortezomib, Carfilzomib), HDAC-inhibitors (Panobinostat,Vorinostat), DNA methyl transferase inhibitors, dexamethasone, bromo andextra terminal family members inhibitors and indoleamine 2,3-dioxygenaseinhibitors.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with one or more additionalagents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodiumhyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603,Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S, 3S, 4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compound of the invention can be administeredin combination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided compound mayalso be combined with include: a treatment for Alzheimer's Disease suchas donepezil and rivastigmine; a treatment for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine,pergolide, trihexyphenidyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., Avonex® andRebif®), glatiramer acetate, and mitoxantrone; a treatment for asthmasuch as albuterol and montelukast; an agent for treating schizophreniasuch as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

Biological drugs, such as antibodies and cytokines, used as anticancerangents, can be combined with the compounds of the invention. Inaddition, drugs modulating microenvironment or immune responses can becombined with the compounds of the invention. Examples of such drugs areanti-Her2 antibodies, anti-CD20 antibodies, anti-CTLA1, anti-PD-1,anti-PDL1, and other immunotherapeutic drugs.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with theotheringredients. If the active compound is substantially insoluble, itcan be milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

The compounds of the invention can be provided with or used incombination with a companion diagnostic. As used herein, the term“companion diagnostic” refers to a diagnostic device useful fordetermining the safe and effective use of a therapeutic agent. Forexample, a companion diagnostic may be used to customize dosage of atherapeutic agent for a given subject, identify appropriatesubpopulations for treatment, or identify populations who should notreceive a particular treatment because of an increased risk of a seriousside effect.

In some embodiments, the companion diagnostic is used to monitortreatment response in a patient. In some embodiments, the companiondiagnostic is used to identify a subject that is likely to benefit froma given compound or therapeutic agent. In some embodiments, thecompanion diagnostic is used to identify a subject having an increasedrisk of adverse side effects from administration of a therapeutic agent,compared to a reference standard. In some embodiments, the companiondiagnostic is an in vitro diagnostic or imaging tool selected from thelist of FDA cleared or approved companion diagnostic devices. In someembodiments, the companion diagnostic is selected from the list of teststhat have been cleared or approved by the Center for Devices andRadiological Health.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating LSD1 in tissue samples,including human, and for identifying LSD1 ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes LSD1assays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention.

An “isotopically” or “radio-labeled” compound is a compound of theinvention where one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind LSD1 by monitoring its concentrationvariation when contacting with LSD1, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to LSD1(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to LSD1 directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof LSD1 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 14-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)methyl]benzoicacid

Step 1: tert-butyl3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate

To a solution of tert-butyl 3-formylazetidine-1-carboxylate (556 mg,3.00 mmol, Alfa Aesar: Cat# H52794) and 2-phenylcyclopropanaminehydrochloride (600. mg, 3.54 mmol, trans, racemic, J&W PharmLab:Cat#20-0073 S, Lot: JW152-128A) in DCM (10 mL) was added acetic acid(510 μL, 9.0 mmol). The resulting yellow solution was stirred at roomtemperature overnight then Na(OAc)₃BH (1.9 g, 9.0 mmol) was added. Thereaction mixture was stirred at room temperature for 1 h then dilutedwith DCM, washed with saturated Na₂CO₃, water and brine. The organiclayer was dried over Na₂SO₄ then concentrated. The residue was purifiedon silica gel column eluting with 0 to 100% EtOAc/Hexanes to give thedesired product (513 mg, 57%) as a light yellow oil. LC-MS calculatedfor C₁₄H₁₉N₂O₂ (M-^(t)Bu+2H)⁺: m/z=247.1; found 247.2.

Step 2: tert-butyl3-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}azetidine-1-carboxylate

To a solution of tert-butyl3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxylate (187mg, 0.618 mmol) in DCM (5 mL) at 0° C. was added triethylamine (0.431mL, 3.09 mmol), followed by dropwise addition of trifluoroaceticanhydride (114 μL, 0.804 mmol). The resulting yellow solution wasstirred at 0° C. for 1 h then quenched with saturated NaHCO₃ solutionand extracted with DCM. The combined extracts were dried over Na₂SO₄then concentrated. The residue was purified on silica gel column elutingwith 0 to 60% EtOAc/Hexanes to give the desired product (228 mg, 93%) asa yellow oil. LC-MS calculated for C₁₆H₁₈F₃N₂O₃(M-^(t)Bu+2H)⁺:m/z=343.1; found 343.2.

Step 3:N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl3-{[(trans-2-phenylcyclopropyl)-(trifluoroacetyl)amino]methyl}azetidine-1-carboxylate(228 mg, 0.572 mmol) in DCM (3 mL) was added TFA (3 mL). The resultinglight yellow solution was stirred at room temperature for 1 h thenconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₁₅H₁₈F₃N₂O (M+H)⁺: m/z=299.1; found299.2.

Step 4: methyl4-[(3-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}azetidin-1-yl)methyl]benzoate

To a solution ofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(57 mg, 0.19 mmol) in acetonitrile (3 mL) was added K₂CO₃ (50 mg, 0.38mmol), followed by methyl 4-bromomethylbenzoate (52 mg, 0.23 mmol). Theresulting mixture was stirred at room temperature for 2.5 h then dilutedwith water and extracted with DCM. The combined extracts were dried overNa₂SO₄ then concentrated. The residue was purified on silica gel columneluting with 0 to 60% EtOAc/Hexanes to give the desired product (27 mg,32%) as a clear oil. LC-MS calculated for C₂₄H₂₆F₃N₂O₃(M+H)⁺: m/z=447.2;found 447.2.

Step 5:4-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)methyl]benzoicacid

To a solution of methyl4-[(3-{[(trans-2-phenylcyclopropyl)-(trifluoroacetyl)amino]methyl}azetidin-1-yl)methyl]benzoate(27 mg, 0.06 mmol) in THF (1 mL) and MeOH (1 mL) was added 0.5 M sodiumhydroxide in water (1.2 mL, 0.6 mmol). The resulting mixture was warmedto 50° C. and stirred for 1 h at which time LC-MS indicated the reactionwas complete to give the desired product. The reaction mixture wascooled to room temperature then diluted with MeOH and purified by prep.HPLC (pH=2, acetonitrile/water+TFA) to give the product in the form ofTFA salt as a white solid. LC-MS calculated for C₂₁H₂₅N₂O₂ (M+H)⁺:m/z=337.2; found 337.2.

Example 2N-{[1-(4-Fluorobenzyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor Example 1 with 1-(chloromethyl)-4-fluoro-benzene replacing methyl4-bromomethylbenzoate in Step 4. The product was purified by prep. HPLC(pH=2, acetonitrile/water+TFA) to give the product in the form of TFAsalt as a white solid. LC-MS calculated for C₂₀H₂₄FN₂ (M+H)⁺: m/z=311.2;found 311.1.

Example 34-({4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}methyl)benzoicacid

Step 1: methyl 4-[(4-oxopiperidin-1-yl)methyl]benzoate

A mixture of piperidin-4-one hydrochloride hydrate (154 mg, 1.00 mmol,Aldrich, Cat#151769), methyl 4-bromomethylbenzoate (230 mg, 1.00 mmol)and K₂CO₃ (346 mg, 2.51 mmol) in acetonitrile (2 mL) was stirred at roomtemperature overnight. The reaction mixture was diluted with water thenextracted with DCM. The combined extracts were dried over Na₂SO₄ thenconcentrated to give the desired product as a colorless oil which wasused in the next step without further purification. LC-MS calculated forC₁₄H₁₈NO₃ (M+H)⁺: m/z=248.1; found 248.1.

Step 2: methyl4-({4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}methyl)benzoate

To a solution of 2-phenylcyclopropanamine hydrochloride (30. mg, 0.17mmol, trans, racemic, Acros, Cat#130470050) and methyl4-[(4-oxopiperidin-1-yl)methyl]benzoate (43 mg, 0.17 mmol) in DCM (2 mL)was added acetic acid (30. μL, 0.52 mmol). The resulting yellow solutionwas stirred at room temperature for 2 h then Na(OAc)₃BH (110 mg, 0.52mmol) was added. The reaction mixture was stirred at room temperaturefor 1 h then diluted with DCM and washed with saturated Na₂CO₃, waterand brine. The organic layer was dried over Na₂SO₄ then concentrated.The residue was used in the next step without further purification.LC-MS calculated for C₂₃H₂₉N₂O₂ (M+H)⁺: m/z=365.2; found 365.1.

Step 3:4-({4-[(trans-2-phenylcyclopropyl)amino]piperidin-1-yl}methyl)benzoicacid

The crude product from Step 2 was dissolved in THF (1 mL) and MeOH (1mL) then 2.0 M sodium hydroxide in water (0.43 mL, 0.87 mmol) was added.The resulting mixture was stirred at 50° C. for 1 h at which time LC-MSindicated the reaction was complete to give the desired product. Thereaction mixture was cooled to room temperature then diluted with MeOHand purified by prep. HPLC (pH=10, acetonitrile/water+NH₄OH) to give theproduct in the form of ammonium salt as a white solid. LC-MS calculatedfor C₂₂H₂₇N₂O₂ (M+H)⁺: m/z=351.2; found 351.3.

Example 43-({4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}methyl)benzoicacid

This compound was prepared using procedures analogous to those describedfor Example 3 with methyl 3-(bromomethyl)benzoate replacing methyl4-bromomethylbenzoate in Step 1. The product was purified by prep. HPLC(pH=2, acetonitrile/water+TFA) to give the desired product in the formof TFA salt as a white solid, LC-MS calculated for C₂₂H₂₇N₂O₂ (M+H)⁺:m/z=351.2; found 351.2.

Example 51-(4-Fluorobenzyl)-N-(trans-2-phenylcyclopropyl)piperidin-4-amine

This compound was prepared using procedures analogous to those describedfor Example 3 with 1-(chloromethyl)-4-fluoro-benzene replacing methyl4-bromomethylbenzoate in Step 1. The product was purified by prep. HPLC(pH=10, acetonitrile/water+NH₄OH) to give the product in the form offree base as a yellow oil. LC-MS calculated for C₂₁H₂₆FN₂ (M+H)⁺:m/z=325.2; found 325.2.

Example 64-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)methyl]benzonitrile

To a solution ofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(20 mg, 0.07 mmol, prepared as described in Example 1, Step 3) and4-formylbenzonitrile (13 mg, 0.10 mmol) in THF (1.5 mL) was added aceticacid (17 μL, 0.30 mmol). The reaction mixture was stirred at roomtemperature overnight then sodium triacetoxyborohydride (64 mg, 0.30mmol) was added. The mixture was stirred at room temperature for 1 hthen 2N NaOH in water (1 mL) and MeOH (1 mL) were added. The resultingmixture was stirred at 40° C. for 1 h then cooled to room temperature,filtered and purified by prep. HPLC (pH=10, acetonitrile/water+NH₄OH) toafford the desired product. LC-MS calculated for C₂₁H₂₄N₃(M+H)⁺:m/z=318.2; found 318.2.

Example 73-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)methyl]benzonitrile

This compound was prepared using procedures analogous to those describedfor Example 6 with 3-cyanobenzaldehyde replacing 4-formylbenzonitrile.LC-MS calculated for C₂₁H₂₄N₃ (M+H)⁺: m/z=318.2; found 318.3.

Example 8(1-(3-Fluorobenzoyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile

Step 1: 1-tert-butyl 4-methyl4-(cyanomethyl)piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate(0.97 g, 4.0 mmol) in THF (20 mL) at −40° C. was added 2.0 M LDA in THF(2.8 mL, 5.6 mmol) dropwise. The resulting mixture was stirred at −40°C. for 30 min then bromoacetonitrile (0.44 mL, 6.4 mmol) was added. Thereaction mixture was stirred at −40° C. for 2 h then quenched withwater. The mixture was warmed to room temperature then diluted withEtOAc, washed with water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with EtOAc in hexane(0-30%) to give the desired product. LC-MS calculated for C₁₀H₁₅N₂O₄(M-^(t)Bu+2H)⁺: m/z=227.1; found 227.2.

Step 2: 1-(tert-Butoxycarbonyl)-4-(cyanomethyl)piperidine-4-carboxylicacid

To a solution of 1-tert-butyl 4-methyl4-(cyanomethyl)piperidine-1,4-dicarboxylate (0.60 g, 2.1 mmol) in THF(4.0 mL)/MeOH (4.0 mL)/water (1.0 mL) was added lithium hydroxide(monohydrate, 0.44 g, 11 mmol). The reaction mixture was stirred at roomtemperature for 2 h then acidified with cold 1 N HCl and extracted withEtOAc. The extract was washed with water, brine, dried over Na₂SO₄,filtered and concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₉H₁₃N₂O₄ (M-^(t)Bu+2H)⁺:m/z=213.1; found 213.1.

Step 3: tert-Butyl4-(cyanomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of1-(tert-butoxycarbonyl)-4-(cyanomethyl)piperidine-4-carboxylic acid(0.50 g, 1.9 mmol) and triethylamine (0.52 mL, 3.7 mmol) in THF (6 mL)at 0° C. was added ethyl chloroformate (0.21 mL, 2.2 mmol). Theresulting mixture was stirred for 30 min then filtered and washed withTHF (2 mL). The filtrate was cooled to 0° C. and then sodiumtetrahydroborate (0.14 g, 3.7 mmol) in methanol (1 mL)/water (1 mL) wasadded. The mixture was warmed to room temperature then stirred for 30min. The mixture was diluted with EtOAc, washed with saturated NaHCO₃,water and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₉H₁₅N₂O₃ (M-^(t)Bu+2H)⁺: m/z=199.1;found 199.1.

Step 4: tert-Butyl 4-(cyanomethyl)-4-formylpiperidine-1-carboxylate

To a solution of tert-butyl4-(cyanomethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (400.0 mg,1.573 mmol) in DCM (8 mL) was added Dess-Martin periodinane (1.0 g, 2.4mmol). The resulting mixture was stirred at room temperature for 3 hthen saturated Na₂S₂O₃ aqueous solution was added and stirred for 10min. The mixture was diluted with DCM, then washed with 1N NaOH, waterand brine. The organic layer was dried over Na₂SO₄, filtered and thenconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with EtOAc in hexane (0-30%) to give thedesired product. LC-MS calculated for C₉H₁₃N₂O₃ (M-^(t)Bu+2H)⁺:m/z=197.1; found 197.1.

Step 5: tert-Butyl4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate

To a solution of tert-butyl4-(cyanomethyl)-4-formylpiperidine-1-carboxylate (180.0 mg, 0.7134 mmol)and 2-phenylcyclopropanamine (114 mg, 0.856 mmol, trans, racemic, J&WPharmLab: Cat#20-0073S) in DCM (3.0 mL) was added acetic acid (0.061 mL,1.1 mmol). The mixture was stirred at r.t. for 2 h then sodiumtriacetoxyborohydride (300 mg, 1.4 mmol) was added. The resultingmixture was stirred at r.t. for 2 h then diluted with DCM, and washedwith saturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with methanol in methylenechloride (0-8%) to give the desired product. LC-MS calculated forC₂₂H₃₂N₃O₂ (M+H)⁺: m/z=370.2; found 370.3.

Step 6: tert-Butyl4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

To a solution of tert-butyl4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate(0.18 g, 0.49 mmol) and DIEA (0.17 mL, 0.97 mmol) in DCM (2.4 mL) at 0°C. was added dropwise trifluoroacetic anhydride (0.08 mL, 0.58 mmol).The mixture was warmed to room temperature and stirred for 1 h thendiluted with DCM, washed with saturated NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with EtOAc in hexane (0-20%) to give the desired product. LC-MScalculated for C₂₀H₂₃F₃N₃O₃(M-^(t)Bu+2H)⁺: m/z=410.2; found 410.1.

Step 7: N-{[4-(Cyanomethyl)piperidin-4-yl]methyl}-2, 2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide

To a solution of tert-butyl4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate(0.16 g, 0.34 mmol) in DCM (0.2 mL) was added 4.0 M hydrogen chloride indioxane (0.8 mL, 3.2 mmol). The resulting mixture was stirred at roomtemperature for 30 min then concentrated. The residue was used in thenext step without further purification. LC-MS calculated for C₁₉H₂₃F₃N₃O(M+H)⁺: m/z=366.2; found 366.1.

Step 8:(1-(3-Fluorobenzoyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile

To a solution ofN-{[4-(cyanomethyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(15.0 mg, 0.0410 mmol) and triethylamine (23 μL, 0.16 mmol) in DCM (0.4mL) at 0° C. was added 3-fluorobenzoyl chloride (9.8 μL, 0.082 mmol).The mixture was stirred for 30 min then concentrated. The residue wasdissolved in methanol (1 mL) and THF (1 mL) then 1 N NaOH (1.0 mL) wasadded. The mixture was stirred at 40° C. for 2 h then cooled to roomtemperature and purified by prep. HPLC (pH=2, acetonitrile/water+TFA) toafford the desired product as a TFA salt. LC-MS calculated forC₂₄H₂₇FN₃O (M+H)⁺: m/z=392.2; found 392.2.

Example 9(1-(3-Fluorobenzyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile

To a solution ofN-{[4-(cyanomethyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(17.9 mg, 0.0490 mmol, prepared as described in Example 8, Step 7) inDCM (0.5 mL) was added 3-fluorobenzaldehyde (12 mg, 0.098 mmol). Themixture was stirred at room temperature for 1 h then sodiumtriacetoxyborohydride (21 mg, 0.098 mmol) was added. The reactionmixture was stirred at room temperature for 2 h then diluted with DCM,and washed with saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was dissolvedin THF (1 mL) and methanol (1 mL) then 1 N NaOH (1 mL) was added. Theresulting mixture was stirred at 40° C. for 4 h then cooled to roomtemperature and purified by prep. HPLC (pH=2, acetonitrile/water+TFA) toafford the desired product as a TFA salt. LC-MS calculated for C₂₄H₂₉FN₃(M+H)⁺: m/z=378.2; found 378.2.

Example 10(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

To a mixture of phosgene in toluene (15 wt % in toluene, 60 μL, 0.1mmol, Aldrich, cat#748684) was added a solution of(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg,0.1 mmol, prepared as disclosed in the literature such as WO2008/157752) and triethylamine (30 μL, 0.2 mmol) in THF (2 mL). Theresulting mixtures was stirred at room temperature for 1 h thenconcentrated under reduced pressure. To the residue was added a solutionofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(20 mg, 0.05 mmol, prepared as described in Example 1, Step 3) andtriethylamine (20 μL, 0.1 mmol) in acetonitrile (1 mL). The reactionmixture was stirred at room temperature for 30 min then 2N NaOH in water(1 mL) was added, followed by MeOH (1 mL). The resulting mixture wasstirred at 30° C. for 1 h then cooled to room temperature and purifiedby prep. HPLC (pH=10, acetonitrile/water+NH₄OH) to afford the desiredproduct. LC-MS calculated for C₂₈H₄₁N₄O₃ (M+H)⁺: m/z=481.3; found 481.3.

Example 11(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 10 with(5S)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one(prepared using similar methods as disclosed in the literature such asWO 2008/157752) replacing(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MScalculated for C₂₈H₄₁N₄O₃ (M+H)⁺: m/z=481.3; found 481.3.

Example 121-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]piperidine-4-carbonitrile

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 10 with piperidine-4-carbonitrile replacing(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MScalculated for C₂₀H₂₇N₄O (M+H)⁺: m/z=339.2; found 339.2.

Example 13Trans-2-phenyl-N-[(1-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}azetidin-3-yl)methyl]cyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 10 with 4-(trifluoromethyl)piperidinereplacing(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MScalculated for C₂₀H₂₇F₃N₃O (M+H)⁺: m/z=382.2; found 382.2.

Example 14N-({1-[(3-Phenoxypiperidin-1-yl)carbonyl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 10 with 3-phenoxypiperidine replacing(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MScalculated for C₂₅H₃₂N₃O₂ (M+H)⁺: m/z=406.2; found 406.2.

Example 15N-({1-[(3-Methoxypiperidin-1-yl)carbonyl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 10 with 3-methoxypiperidine replacing(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MScalculated for C₂₀H₃₀N₃O₂ (M+H)⁺: m/z=344.2; found 344.1.

Example 164-Phenyl-1-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]piperidine-4-carbonitrile

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 10 with 4-phenylpiperidine-4-carbonitrilehydrochloride replacing(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MScalculated for C₂₆H₃₁N₄O (M+H)⁺: m/z=415.2; found 415.2.

Example 174-Phenyl-1-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]piperidin-4-ol

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 10 with 4-phenylpiperidin-4-ol replacing(5R)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC-MScalculated for C₂₅H₃₂N₃O₂ (M+H)⁺: m/z=406.2; found 406.2.

Example 18N-({1-[(5-Fluoro-1,2-dihydro-spiro[indole-3,4′-piperidin]-1′-yl)carbonyl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine

To a mixture of phosgene in toluene (15 wt % in toluene, 60 μL, 0.1mmol, Aldrich, cat#748684) was added a solution of tert-butyl5-fluorospiro[indole-3,4′-piperidine]-1(2H)-carboxylate hydrochloride(30 mg, 0. 1 mmol, prepared as disclosed in the literature such as WO2008/157752) and triethylamine (30 μL, 0.2 mmol) in THF (2 mL). Theresulting mixtures was stirred at room temperature for 1 h thenconcentrated under reduced pressure. To the residue was added a solutionofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(20 mg, 0.05 mmol, prepared as described in Example 1, Step 3) andtriethylamine (20 μL, 0.1 mmol) in acetonitrile (1 mL). The reactionmixture was stirred at room temperature for 30 min then quenched withsaturated aqueous NaHCO₃, and extracted with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was dissolved inacetonitrile (1 mL) then TFA (1 mL) was added. The resulting mixture wasstirred at room temperature for 1 h then concentrated. The residue wasdissolved in THF (1 mL) and MeOH (1 mL) then 2N aqueous NaOH (0.5 mL)was added. The reaction mixture was stirred at 30° C. for 1 h thencooled to room temperature and purified by prep. HPLC (pH=10,acetonitrile/water+NH₄OH) to afford the desired product. LC-MScalculated for C₂₆H₃₂FN₄O (M+H)⁺: m/z=435.3; found 435.3.

Example 19N-(2-Fluorophenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide

To a solution ofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(20 mg, 0.05 mmol, prepared as described in Example 1, Step 3) andtriethylamine (30 μL, 0.2 mmol) in acetonitrile (1 mL) was added1-fluoro-2-isocyanatobenzene (10 mg, 0.1 mmol). The reaction mixture wasstirred at room temperature for 1 h then 2N aqueous NaOH (1 mL) wasadded, followed by MeOH (1 mL). The reaction mixture was stirred at 30°C. for 1 h then cooled to room temperature, filtered and purified byprep. HPLC (pH=10, acetonitrile/water+NH₄OH) to afford the desiredproduct. LC-MS calculated for C₂₀H₂₃FN₃O (M+H)⁺: m/z=340.2; found 340.1.

Example 20N-(3-Fluorophenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 19 with 1-fluoro-3-isocyanatobenzenereplacing 1-fluoro-2-isocyanatobenzene. LC-MS calculated for C₂₀H₂₃FN₃O(M+H)⁺: m/z=340.2; found 340.1.

Example 21N-(4-Fluorophenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 19 with 1-fluoro-4-isocyanatobenzenereplacing 1-fluoro-2-isocyanatobenzene. LC-MS calculated for C₂₀H₂₃FN₃O(M+H)⁺: m/z=340.2; found 340.1.

Example 22N-(4-Methoxyphenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 19 with 1-isocyanato-4-methoxybenzenereplacing 1-fluoro-2-isocyanatobenzene. LC-MS calculated for C₂₁H₂₆N₃O₂(M+H)⁺: m/z=352.2; found 352.2.

Example 23N-(3-Methoxyphenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 19 with 1-isocyanato-3-methoxybenzenereplacing 1-fluoro-2-isocyanatobenzene. LC-MS calculated for C₂₁H₂₆N₃O₂(M+H)⁺: m/z=352.2; found 352.2.

Example 24N-(2-Methoxyphenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 19 with 1-isocyanato-2-methoxybenzenereplacing 1-fluoro-2-isocyanatobenzene. LC-MS calculated for C₂₁H₂₆N₃O₂(M+H)⁺: m/z=352.2; found 352.1.

Example 254-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]benzonitrile

To a solution ofN-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide(20 mg, 0.05 mmol, prepared as described in Example 1, Step 3) andtriethylamine (30 μL, 0.2 mmol) in acetonitrile (1 mL) was added4-cyanobenzoyl chloride (20 mg, 0.1 mmol). The reaction mixture wasstirred at room temperature for 1 h then 2N NaOH in water (1 mL) wasadded, followed by MeOH (1 mL). The resulting mixture was stirred at 30°C. for 1 h then cooled to room temperature, filtered and purified byprep. HPLC (pH=10, acetonitrile/water+NH₄OH) to afford the desiredproduct. LC-MS calculated for C₂₁H₂₂N₃O (M+H)⁺: m/z=332.2; found 332.1.

Example 263-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]benzonitrile

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 25 with 3-cyanobenzoyl chloride replacing4-cyanobenzoyl chloride. LC-MS calculated for C₂₁H₂₂N₃O (M+H)⁺:m/z=332.2; found 332.1.

Example 27N-{[1-(3-Methoxybenzoyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 25 with 3-methoxy-benzoyl chloridereplacing 4-cyanobenzoyl chloride. LC-MS calculated for C₂₁H₂₅N₂O₂(M+H)⁺: m/z=337.2; found 337.1.

Example 28N-{[1-(4-Fluorobenzoyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 25 with 4-fluoro-benzoyl chloride replacing4-cyanobenzoyl chloride. LC-MS calculated for C₂₀H₂₂FN₂O (M+H)⁺:m/z=325.2; found 325.1.

Example 29N-{[1-(3-Fluorobenzoyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 25 with 3-fluoro-benzoyl chloride replacing4-cyanobenzoyl chloride. LC-MS calculated for C₂₀H₂₂FN₂O (M+H)⁺:m/z=325.2; found 325.1.

Example 30Trans-2-phenyl-N-[(1-{[4-(trifluoromethoxy)phenyl]sulfonyl}azetidin-3-yl)methyl]cyclopropanamine

This compound was prepared using procedures analogous to those describedfor the synthesis of Example 25 with 4-(trifluoromethoxy)benzenesulfonyl chloride replacing 4-cyanobenzoyl chloride. LC-MS calculatedfor C₂₀H₂₂F₃N₂O₃S (M+H)⁺: m/z=427.1; found 427.0.

Example 311-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: 1-tert-butyl 4-methyl4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate

To a solution of N,N-diisopropylamine (4.9 mL, 35 mmol) intetrahydrofuran (80 mL) at −78° C. was added n-butyllithium (2.5 M inhexanes, 14 mL, 35 mmol). The resulting mixture was warmed to −20° C.and stirred for 10 min then cooled to −78° C. and a solution of1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (AstaTech,cat#B56857: 6.08 g, 25.0 mmol) in THF (10 mL) was slowly added. Thereaction mixture was slowly warmed to −40° C. and stirred for 1 h. Themixture was then cooled to −78° C. and α-bromo-4-fluorotoluene (4.9 mL,40. mmol) was added. The reaction mixture was stirred at −78° C. for 1 hthen quenched with saturated NH₄Cl, warmed to room temperature anddiluted with ethyl ether. The mixture was then washed with water, brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with EtOAc inhexane (0-20%) to give the desired product (6.5 g, 74%). LC-MScalculated for C₁₅H₁₉FNO₄ (M-^(t)Bu+2H)⁺: m/z=296.1; found 296.1.

Step 2: tert-butyl4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl4-(4-fluorobenzyl)piperidine-1,4-dicarboxylate (6.5 g, 18 mmol) intetrahydrofuran (90 mL) at 0° C. was added LiAlH₄ (1M in THF, 24 mL, 24mmol) slowly. The resulting mixture was stirred at 0° C. for 30 min thenwater (0.9 mL) was added, followed by NaOH (15 wt % in water, 0.9 mL)and water (0.9 mL). The mixture was stirred for 20 min then filtered andwashed with THF. The filtrate was concentrated and the residue (5.8 g,97%) was used in the next step without further purification. LC-MScalculated for C₁₄H₁₉FNO₃ (M-^(t)Bu+2H)⁺: m/z=268.1; found 268.1.

Step 3: tert-butyl 4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate

A solution of dimethyl sulfoxide (4.3 mL, 60. mmol) in methylenechloride (6 mL) was added to a solution of oxalyl chloride (2.6 mL, 30mmol) in methylene chloride at −78° C. over 10 min and then theresulting mixture was warmed to −60° C. over 25 min. A solution oftert-butyl 4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate(5.2 g, 16 mmol) in methylene chloride (6 mL) was slowly added and thenwarmed to −45° C. over 30 mins. N,N-Diisopropylethylamine (21 mL, 120mmol) was then added and the mixture was warmed to 0° C. over 15 min.The mixture was poured into a cold 1 N HCl aqueous solution and thenextracted with ethyl ether. The combined extracts were dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with EtOAc in hexane(0-20%) to give the desired product (4.3 g, 83%). LC-MS calculated forC₁₄H₁₇FNO₃ (M-^(t)Bu+2H)⁺: m/z=266.1; found 266.1.

Step 4: tert-butyl4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-fluorobenzyl)-4-formylpiperidine-1-carboxylate (4.2 g, 13 mmol) and(1R,2S)-2-phenylcyclopropanamine (1.96 g, 14.7 mmol) (prepared usingprocedures as described in Bioorg. Med. Chem. Lett., 2011, 21, 4429) in1,2-dichloroethane (50 mL) was added acetic acid (1.1 mL, 20. mmol). Theresulting mixture was stirred at room temperature for 2 h then sodiumtriacetoxyborohydride (5.7 g, 27 mmol) was added. The reaction mixturewas stirred at room temperature for 5 h then diluted with methylenechloride, washed with 1 N NaOH aqueous solution, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with MeOH in DCM (0-6%) to give the desired product (5.0 g,87%). LC-MS calculated for C₂₇H₃₆FN₂O₂(M+H)⁺: m/z=439.3; found 439.2.

Step 5: tert-butyl4-(4-fluorobenzyl)-4-{[(1R,2S)-2-phenylcyclopropyl-(trifluoroacetyl)amino]-methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (2.08 mL, 14.7 mmol) was added to a solutionof tert-butyl4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(4.3 g, 9.8 mmol) and N,N-diisopropylethylamine (4.3 mL, 24 mmol) inmethylene chloride (40 mL) at 0° C. The resulting mixture was stirred at0° C. for 1 h then diluted with ether and washed with 1 N HCl, water andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated.

The residue was purified by flash chromatography on a silica gel columneluting with EtOAc in hexanes (0-30%) to give the desired product (4.6g, 88%). LC-MS calculated for C₂₅H₂₇F₄N₂O₃ (M-^(t)Bu+2H)⁺: m/z=479.2;found 479.2.

Step 6:2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

Hydrogen chloride (4 M in 1,4-dioxane, 20 mL, 80 mmol) was added to asolution of tert-butyl4-(4-fluorobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-1-carboxylate(4.6 g, 8.6 mmol) in methylene chloride (6 mL). The resulting mixturewas stirred at room temperature for 30 min then concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₂₄H₂₇F₄N₂O (M+H)⁺: m/z=435.2; found 435.2.

Step 7: methyl 1-(hydroxymethyl)cyclopropanecarboxylate

Isobutyl chloroformate (0.61 mL, 4.7 mmol) was added to a solution of1-(methoxycarbonyl)cyclopropanecarboxylic acid (Alfa Aesar, cat#H25828:0.57 g, 3.9 mmol) and triethylamine (1.1 mL, 7.8 mmol) intetrahydrofuran (10 mL) at 0° C. The resulting mixture was stirred at 0°C. for 30 min then filtered and washed with THF (2 mL). The filtrate wascooled to 0° C. and then a solution of sodium tetrahydroborate (0.30 g,7.9 mmol) in water (2 mL) was added. The reaction mixture was stirredfor 30 min then diluted with ethyl acetate, washed with saturated NaHCO₃aqueous solution, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue (0.46 g) was used in thenext step without further purification.

Step 8: methyl 1-formylcyclopropanecarboxylate

Dimethyl sulfoxide (0.57 mL, 8.0 mmol) in methylene chloride (0.8 mL)was added to a solution of oxalyl chloride (0.34 mL, 4.0 mmol) inmethylene chloride (5 mL) at −78° C. over 10 min. The resulting mixturewas warmed to −60° C. over 25 min then a solution of methyl1-(hydroxymethyl)cyclopropanecarboxylate (0.40 g, 3.1 mmol) in methylenechloride (5 mL) was slowly added. The mixture was warmed to −45° C. over30 mins then N,N-diisopropylethylamine (2.8 mL, 16 mmol) was added andthe mixture was warmed to 0° C. over 15 min. The reaction mixture waspoured into a cold 1 N HCl aqueous solution and extracted with diethylether. The combined extracts were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with EtOAc in hexane (0-20%) to give thedesired product (0.30 g, 76%).

Step 9: methyl1-[(4-(4-fluorobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]-methyl}piperidin-1-yl)methyl]cyclopropanecarboxylate

N,N-Diisopropylethylamine (0.19 mL, 1.1 mmol) was added to a mixture of2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Step 6: 400.0 mg, 0.92 mmol) in methylene chloride (4 mL). Theresulting mixture was stirred for 5 min and then methyl1-formylcyclopropanecarboxylate (153 mg, 1.20 mmol) was added. Thereaction mixture was stirred at room temperature for 1 h then sodiumtriacetoxyborohydride (0.58 g, 2.8 mmol) was added. The mixture wasstirred at room temperature for 4 h then diluted with methylenechloride, washed with 1 N NaOH, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with methanol inDCM (0-6%) to give the desired product (0.45 g, 89%). LC-MS calculatedfor C₃₀H₃₅F₄N₂O₃(M+H)⁺: m/z=547.3; found 547.3.

Step 10:1-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

The product from Step 9 was dissolved in MeOH/THF (1.0/0.6 mL) and thenNaOH (15 wt % in water, 3.0 mL) was added. The reaction mixture wasstirred at 40° C. overnight then cooled to room temperature and purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₂₇H₃₄FN₂O₂ (M+H)⁺: m/z=437.3;found 437.2. ¹H NMR (500 MHz, DMSO) δ 7.35-7.28 (m, 2H), 7.26-7.20 (m,3H), 7.20-7.10 (m, 4H), 3.41-3.29 (m, 4H), 3.28-3.09 (m, 4H), 2.94 (br,1H), 2.84 (s, 2H), 2.60-2.51 (m, 1H), 1.84-1.67 (m, 4H), 1.63-1.52 (m,1H), 1.37-1.26 (m, 3H), 1.17-1.09 (m, 2H).

Example 321-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

Step 1: methyl 1-formylcyclobutanecarboxylate

To a solution of dimethyl cyclobutane-1,1-dicarboxylate (Alfa Aesar,cat#L12250: 1.0 g, 6.0 mmol) in methylene chloride (15 mL) at −78° C.was added 1.0 M diisobutylaluminum hydride in toluene (12.0 mL, 12.0mmol). The reaction mixture was stirred at −78° C. for 45 min, andquenched with slow addition of 1 M HCl. The resulting mixture was warmedto room temperature and stirred for another 30 min. The organic layerwas separated, washed with brine, dried over Na₂SO₄, and concentrated.The crude material was purified via column chromatography (0 to 20%EtOAc in hexanes) to give the product as a colorless oil (330 mg, 39%).¹H NMR (400 MHz, CDCl₃) δ 9.78 (s, 1H), 3.79 (s, 3H), 2.48 (t, J=8.0 Hz,4H), 2.13-1.87 (m, 2H).

Step 2:1-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

A mixture of methyl 1-formylcyclobutanecarboxylate (20. mg, 0.14 mmol),acetic acid (6 μL, 0.10 mmol) and2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 31, Step 6: 40.0 mg, 0.0921 mmol) in methylene chloride (2 mL)was stirred at room temperature for 2 h and then sodiumtriacetoxyborohydride (64 mg, 0.30 mmol) was added. The reaction mixturewas stirred at room temperature overnight then diluted with methylenechloride, washed with 1 N NaOH, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was dissolvedin MeOH/THF (0.5/0.5 mL) and then 6 N NaOH (1.0 mL) was added. Theresulting mixture was stirred at 40° C. overnight then cooled to roomtemperature and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₂₈H₃₆FN₂O₂(M+H)⁺: m/z=451.3; found 451.3.

Example 33trans-4-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclohexanamine

Triethylamine (23 μL, 0.16 mmol) was added to a solution oftrans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (TCIAmerica, cat#B3250: 10.0 mg, 0.0411 mmol),2,2,2-trifluoro-N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 31, Step 6: 14 mg, 0.033 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(27 mg, 0.062 mmol) in N,N-dimethylformamide (0.6 mL). The resultingmixture was stirred at room temperature for 1 h then diluted with ethylacetate, washed with saturated NaHCO₃ aqueous solution, water and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was dissolved in DCM (0.3 mL) and then TFA (0.3 mL) was added.The mixture was stirred at room temperature for 1 h then concentrated.The residue was dissolved in THF/MeOH (0.2 mL/0.2 mL) and then NaOH (15wt % in water, 0.5 mL) was added and the mixture was stirred at 35° C.overnight. The mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₉FN₃O (M+H)⁺: m/z=464.3; found 464.3.

Example 341-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclobutanamine

This compound was prepared using procedures analogous to those describedfor Example 33 with 1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylicacid (Aldrich, cat#630802) replacingtrans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid. Themixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₂₇H₃₅FN₃O(M+H)⁺: m/z=436.3; found 436.3.

Example 351-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: 1-tert-butyl 4-methyl4-(methoxymethyl)piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate(AstaTech, cat#B56857: 2.43 g, 10.0 mmol) in tetrahydrofuran (30 mL) at−40° C. was added lithium diisopropylamide (2 M in THF, 5.8 mL, 12mmol). The resulting mixture was stirred at −40° C. for 30 min thenchloromethyl methyl ether (1.2 mL, 16 mmol) was added. The reactionmixture was stirred at −40° C. for 1 h then quenched with saturatedNH₄Cl aqueous solution and warmed to room temperature. The mixture wasdiluted with ethyl acetate, washed with saturated NaHCO₃ aqueoussolution, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude material was purified via flashchromatography on a silica gel column (0 to 20% EtOAc in hexanes) togive the desired product (2.6 g, 90%). LC-MS calculated for C₉H₁₈NO₃(M-Boc+2H)⁺: m/z=188.1; found 188.1.

Step 2: tert-butyl4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl4-(methoxymethyl)piperidine-1,4-dicarboxylate (2.3 g, 8.0 mmol) intetrahydrofuran (40 mL) at 0° C. was added LiAlH₄ (1 M in THF, 10. mL,10. mmol) slowly. The resulting mixture was stirred at 0° C. for 30 minthen quenched with addition of water (0.1 mL), NaOH (15 wt % in water,0.1 mL) and water (0.1 mL). The mixture was stirred for 10 min thenfiltered and washed with THF. The filtrate was concentrated and theresidue was used in the next step without further purification. LC-MScalculated for C₉H₁₈NO₄ (M-^(t)Bu+2H)⁺: m/z=204.1; found 204.1.

Step 3: tert-butyl 4-formyl-4-(methoxymethyl)piperidine-1-carboxylate

Dimethyl sulfoxide (1.7 mL, 24 mmol) in methylene chloride (2 mL) wasadded to a solution of oxalyl chloride (1.0 mL, 12 mmol) in methylenechloride (3 mL) at −78° C. over 10 min. The resulting mixture was warmedto −60° C. over 25 min then a solution of tert-butyl4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate (1.6 g, 6.0mmol) in methylene chloride (5 mL) was slowly added. The mixture waswarmed to −45° C. over 30 min then triethylamine (6.7 mL, 48 mmol) wasadded. The mixture was warmed to 0° C. over 15 min. The reaction mixturewas then poured into a cold 1 N HCl aqueous solution and extracted withdiethyl ether. The combined extracts were dried over Na₂SO₄, filteredand concentrated. The residue was purified via flash chromatography on asilica gel column eluting with 0 to 20% EtOAc in hexanes to give thedesired product (1.3 g, 84%). LC-MS calculated for C₈H₁₆NO₂ (M-Boc+2H)⁺:m/z=158.1; found 158.1.

Step 4: tert-butyl4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-piperidine-1-carboxylate

A mixture of tert-butyl4-formyl-4-(methoxymethyl)piperidine-1-carboxylate (1.3 g, 5.0 mmol),acetic acid (0.43 mL, 7.5 mmol) and (1R,2S)-2-phenylcyclopropanamine(prepared using procedures as described in Bioorg. Med. Chem. Lett.,2011, 21, 4429: 699 mg, 5.25 mmol) in 1,2-dichloroethane (20 mL) wasstirred at room temperature for 1 h then sodium triacetoxyborohydride(2.1 g, 10. mmol) was added. The resulting mixture was stirred at roomtemperature for 2 h then diluted with methylene chloride, washed withsaturated NaHCO₃ aqueous solution, water and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified via flash chromatography on a silica gel column eluting with 0to 8% methanol in DCM to give the desired product (1.7 g, 91%). LC-MScalculated for C₂₂H₃₅N₂O₃ (M+H)⁺: m/z=375.3; found 375.2.

Step 5: tert-butyl4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl]-(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution oftert-butyl4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(1.7 g, 4.5 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.1 mmol) inmethylene chloride (25 mL) at 0° C. The resulting mixture was stirred atroom temperature for 1 h then diluted with methylene chloride, washedwith sat'd NaHCO₃ aqueous solution, water, and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified via flash chromatography on a silica gel column eluting with 0to 20% EtOAc in hexanes to give the desired product (1.8 g, 84%). LC-MScalculated for C₁₉H₂₆F₃N₂O₂(M-Boc+2H)⁺: m/z=371.2; found 371.1.

Step 6:2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

4.0 M Hydrogen chloride in dioxane (7 mL, 28 mmol) was added to asolution of tert-butyl4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl})-piperidine-1-carboxylate(1.8 g, 3.8 mmol) in methylene chloride (4 mL). The resulting mixturewas stirred at room temperature for 30 min then concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₁₉H₂₆F₃N₂O₂(M+H)⁺: m/z=371.2; found 371.2. The crudeproduct was neutralized to give the free base form of the product whichwas used to obtain the NMR data. ¹H NMR (500 MHz, CD₃OD) δ 7.31-7.26 (m,2H), 7.22-7.17 (m, 1H), 7.12-7.07 (m, 2H), 3.79-3.58 (m, 2H), 3.35-3.32(m, 2H), 3.28-3.22 (m, 1H), 3.19-2.98 (m, 7H), 2.44-2.34 (m, 1H),1.84-1.54 (m, 5H), 1.48-1.37 (m, 1H); ¹³C NMR (126 MHz, CD₃OD) δ 161.74,141.21, 129.63, 127.51, 126.73, 119.39, 76.75, 59.28, 53.29, 42.71,41.54, 39.22, 30.06, 27.95, 20.10.

Step 7: methyl1-[(4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]-methyl}piperidin-1-yl)methyl]cyclopropanecarboxylate

A mixture of methyl 1-formylcyclopropanecarboxylate (Example 31, Step 8:53 mg, 0.41 mmol), acetic acid (17 μL, 0.29 mmol) and2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(100.0 mg, 0.2700 mmol) in methylene chloride (2 mL) was stirred at roomtemperature for 2 h then sodium triacetoxyborohydride (190 mg, 0.88mmol) was added. The mixture was stirred at room temperature for 2 hthen diluted with methylene chloride, washed with 1 N NaOH, water andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified via flash chromatography on asilica gel column eluting with 0 to 6% MeOH in DCM to give the desiredproduct. LC-MS calculated for C₂₅H₃₄F₃N₂O₄(M+H)⁺: m/z=483.2; found483.3.

Step 8:1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

The product from Step 7 was dissolved in MeOH/THF (0.5/0.5 mL) then NaOH(15 wt % in water, 1.0 mL) was added. The resulting mixture was stirredat 40° C. overnight then cooled to room temperature and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₂H₃₃N₂O₃ (M+H)⁺: m/z=373.2; found373.3. ¹H NMR (500 MHz, DMSO) δ 7.33-7.28 (m, 2H), 7.24-7.19 (m, 1H),7.19-7.15 (m, 2H), 3.40 (s, 2H), 3.36-3.31 (m, 5H), 3.30-3.19 (m, 4H),3.14 (s, 2H), 2.92-2.83 (m, 1H), 2.47-2.41 (m, 1H), 1.92-1.71 (m, 4H),1.54-1.41 (m, 1H), 1.37-1.30 (m, 2H), 1.29-1.20 (m, 1H), 1.16-1.09 (m,2H).

Example 361-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

Step 1: methyl1-[(4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]-methyl}piperidin-1-yl)methyl]cyclobutanecarboxylate

A mixture of methyl 1-formylcyclobutanecarboxylate (Example 32, Step 1:200 mg, 1.4 mmol), acetic acid (60 μL, 1.1 mmol) and2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 350 mg, 0.95 mmol) in methylene chloride (7 mL) wasstirred at room temperature for 2 h and then sodiumtriacetoxyborohydride (650 mg, 3.1 mmol) was added. The resultingmixture was stirred at room temperature overnight then diluted withmethylene chloride, washed with 1 N NaOH, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified via flash chromatography on a silica gel column eluting with 0to 6% MeOH in DCM to give the desired product. LC-MS calculated forC₂₆H₃₆F₃N₂O₄(M+H)⁺: m/z=497.3; found 497.3.

Step 2:1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

The product from Step 1 was dissolved in MeOH/THF (2.0/2.0 mL) then 6 NNaOH (1.0 mL) was added. The resulting mixture was stirred at 40° C. for36 h then cooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₃₅N₂O₃ (M+H)⁺: m/z=387.3; found 387.2. ¹H NMR(500 MHz, CD₃CN) δ 7.35-7.29 (m, 2H), 7.27-7.21 (m, 1H), 7.19-7.13 (m,2H), 3.46 (s, 2H), 3.43 (s, 2H), 3.36 (s, 3H), 3.34-3.12 (m, 6H),2.94-2.84 (m, 1H), 2.70-2.60 (m, 1H), 2.56-2.43 (m, 2H), 2.22-1.96 (m,4H), 1.93-1.76 (m, 4H), 1.71-1.59 (m, 1H), 1.33-1.22 (m, 1H).

Example 371-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylicacid

Step 1: 1-tert-butyl 1-methyl cyclopentane-1, 1-dicarboxylate

1,4-Dibromobutane (2.4 mL, 20. mmol) was added to a mixture oftert-butyl methyl malonate (1.74 g, 10.0 mmol), cesium carbonate (9.8 g,30. mmol) and 1-butyl-3-methyl-1H-imidazol-3-ium tetrafluoroborate (0.4g, 2 mmol) in acetonitrile (20 mL). The resulting mixture was stirred atroom temperature overnight then diluted with diethyl ether and filtered.The filtrate was concentrated and the residue was dissolved in diethylether then washed with water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified via flashchromatography on a silica gel column eluting with 0 to 10% EtOAc inhexanes to give the desired product (1.7 g, 75%). LC-MS calculated forC₈H₁₃O₄(M-^(t)Bu+2H)⁺: m/z=173.1; found 173.1.

Step 2: 1-(tert-butoxycarbonyl)cyclopentanecarboxylic acid

To a solution of 1-tert-butyl 1-methyl cyclopentane-1,1-dicarboxylate(1.7 g, 7.4 mmol) in tetrahydrofuran (10 mL)/methanol (5 mL)/water (5mL) was added lithium hydroxide, monohydrate (0.62 g, 15 mmol). Theresulting mixture was stirred at room temperature for 5 h thenconcentrated to remove most of the solvents. The residue was dissolvedin water and washed with ether. The aqueous layer was acidified usingcold 1 N HCl solution then extract with DCM. The combined DCM extractswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the desired compound which was used in the next step withoutfurther purification. LC-MS calculated for C₇H₁₁O₄(M-^(t)Bu+2H)⁺:m/z=159.1; found 159.1.

Step 3: tert-butyl 1-(hydroxymethyl)cyclopentanecarboxylate

Isobutyl chloroformate (1.1 mL, 8.2 mmol) was added to a solution of1-(tert-butoxycarbonyl)cyclopentanecarboxylic acid (1.60 g, 7.47 mmol)and 4-methylmorpholine (0.9 mL, 8.2 mmol) in tetrahydrofuran (20 mL) at−20° C. The resulting mixture was stirred for 30 min then filtered andwashed with THF (4 mL). The filtrate was cooled to −20° C. and thensodium tetrahydroborate (0.56 g, 15 mmol) in water (4 mL) was added. Thereaction mixture was stirred for 30 min then diluted with ethyl acetate,washed with saturated NaHCO₃ aqueous solution, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₇H₁₃O₃(M-^(t)Bu+2H)⁺: m/z=145.1; found 145.1.

Step 4: tert-butyl 1-formylcyclopentanecarboxylate

Dimethyl sulfoxide (1.9 mL, 26 mmol) in methylene chloride (3 mL) wasadded to a solution of oxalyl chloride (1.1 mL, 13 mmol) in methylenechloride (5 mL) at −78° C. over 10 min. The resulting mixture was warmedto −60° C. over 25 min then a solution of tert-butyl1-(hydroxymethyl)cyclopentanecarboxylate (1.4 g, 7.0 mmol) in methylenechloride (5 mL) was slowly added. The mixture was warmed to −45° C. over30 min then N,N-diisopropylethylamine (9.1 mL, 52 mmol) was added. Themixture was warmed to 0° C. over 15 min then poured into a cold 1 N HClaqueous solution and extracted with ethyl ether. The combined extractswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified via flash chromatography on a silica gel column eluting with 0to 20% EtOAc in hexanes to give the desired product (1.0 g, 72%). LC-MScalculated for C₇H₁₁O₃(M-^(t)Bu+2H)⁺: m/z=143.1; found 143.1.

Step 5: tert-butyl1-[(4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)-amino]methyl}piperidin-1-yl)methyl]cyclopentanecarboxylate

To a solution of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 400 mg, 1.00 mmol) and N,N-diisopropylethylamine(0.28 mL, 1.6 mmol) in methylene chloride (8 mL) was added tert-butyl1-formylcyclopentanecarboxylate (280 mg, 1.4 mmol). The resultingmixture was stirred at room temperature for 2 h then sodiumtriacetoxyborohydride (690 mg, 3.2 mmol) was added. The reaction mixturewas stirred at room temperature overnight then diluted with methylenechloride, washed with 1 N NaOH, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedvia flash chromatography on a silica gel column eluting with 0 to 6%MeOH in DCM to give the desired product (0.45 g, 75%). LC-MS calculatedfor C₃₀H₄₄F₃N₂O₄(M+H)⁺: m/z=553.3; found 553.3.

Step 6:1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylicacid

To a solution of tert-butyl1-[(4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl]-(trifluoroacetyl)amino]methyl}piperidin-1-yl)methyl]cyclopentanecarboxylate(450 mg, 0.81 mmol) in methylene chloride (2 mL) was addedtrifluoroacetic acid (2.0 mL, 26 mmol). The resulting mixture wasstirred at room temperature for 4 h then concentrated. The residue wasdissolved in THF/methanol (2 mL/2 mL) and then 6 N NaOH (3.0 mL) wasadded. The resulting mixture was stirred at room temperature overnightthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₄H₃₇N₂O₃ (M+H)⁺:m/z=401.3; found 401.2.

Example 38(1R,2S)—N-[(4-(methoxymethyl)-1-{[(2S)-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)methyl]-2-phenylcyclopropanamine

To a solution of (2S)-1-methylpyrrolidine-2-carboxylic acid (Chem-Impex,cat#06356: 11 mg, 0.088 mmol),2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 16 mg, 0.044 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (46mg, 0.088 mmol) in N,N-dimethylformamide (1 mL) was added triethylamine(31 μL, 0.22 mmol). The resulting mixture was stirred at roomtemperature for 4 h then NaOH (15 wt %, 0.5 mL) was added. The mixturewas stirred at 40° C. overnight then cooled to room temperature andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₃H₃₆N₃O₂ (M+H)⁺:m/z=386.3; found 386.2.

Example 39(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-imidazol-4-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

This compound was prepared using similar procedures as described forExample 38 with 1-methyl-1H-imidazole-4-carboxylic acid (Combi-Blocks,cat#HI-1090) replacing (2S)-1-methylpyrrolidine-2-carboxylic acid. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₃₁N₄O₂ (M+H)⁺: m/z=383.2; found 383.2.

Example 406-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyridazin-3-amine

This compound was prepared using similar procedures as described forExample 38 with 6-aminopyridazine-3-carboxylic acid (Chem-Impex,cat#19168) replacing (2S)-1-methylpyrrolidine-2-carboxylic acid. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₃₀N₅O₂ (M+H)⁺: m/z=396.2; found 396.2. ¹H NMR(500 MHz, CD₃CN) δ 7.75 (d, J=9.5 Hz, 1H), 7.40 (d, J=9.5 Hz, 1H),7.35-7.28 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.13 (m, 2H), 3.80-3.47 (m,6H), 3.37 (s, 3H), 3.36-3.23 (m, 2H), 2.98-2.82 (m, 1H), 2.73-2.60 (m,1H), 1.72-1.54 (m, 5H), 1.35-1.20 (m, 1H).

Example 41(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methylpiperidin-4-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

This compound was prepared using similar procedures as described forExample 38 with 1-methylpiperidine-4-carboxylic acid (AstaTech,cat#64217) replacing (2S)-1-methylpyrrolidine-2-carboxylic acid. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₈N₃O₂ (M+H)⁺: m/z=400.3; found 400.3.

Example 42(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-3-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

1-Methyl-1H-pyrazole-3-carbonyl chloride (Maybridge, cat#CC48302: 12 mg,0.081 mmol) was added to a solution of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl})-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 15.0 mg, 0.040 mmol) and triethylamine (22 μL, 0.16mmol) in methylene chloride (0.5 mL) at 0° C. The resulting mixture wasstirred at room temperature for 3 h then diluted with ethyl acetate,washed with 1 N NaOH, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was dissolved inmethanol/THF (1/1 mL) and then NaOH (15 wt % in water, 1.5 mL) wasadded. The mixture was stirred at 40° C. overnight then cooled to roomtemperature and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₂₂H₃₁N₄O₂ (M+H)⁺: m/z=383.2; found 383.2.

Example 43(1R,2S)—N-({4-(methoxymethyl)-1-[(4-methylpiperazin-1-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

4-Methylpiperazine-1-carbonyl chloride (Aldrich, cat#563250: 99 μL, 0.73mmol) was added to a solution of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 90.0 mg, 0.243 mmol) and N,N-diisopropylethylamine(0.13 mL, 0.73 mmol) in N,N-dimethylformamide (0.8 mL) at roomtemperature. The resulting mixture was stirred at 90° C. overnight thencooled to room temperature and concentrated. The residue was purifiedvia flash chromatography on a silica gel column eluting with 0 to 6%MeOH in DCM to give the desired intermediate. To the solution of theintermediate in MeOH/THF (0.5 mL/0.5 mL) was added NaOH (15 wt % inwater, 1 mL). The mixture was stirred at 40° C. overnight then cooled toroom temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₃₇N₄O₂ (M+H)⁺: m/z=401.3; found 401.3.

Example 441-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: tert-butyl4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate(Synnovator, cat#PBN2011767: 2.50 g, 11.0 mmol), acetic acid (0.94 mL,16 mmol) and (1R,2S)-2-phenylcyclopropanamine (1.54 g, 11.5 mmol) in1,2-dichloroethane (40 mL) was stirred at room temperature for 1 h thensodium triacetoxyborohydride (4.7 g, 22 mmol) was added. The mixture wasstirred at room temperature for 2 h then diluted with methylenechloride, washed with saturated NaHCO₃, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified via flash chromatography on a silica gel column eluting with 0to 8% MeOH in DCM to give the desired product (3.4 g, 90%). LC-MScalculated for C₂₁H₃₃N₂O₂ (M+H)⁺: m/z=345.3; found 345.2.

Step 2: tert-butyl4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-1-carboxylate

Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution oftert-butyl4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(1.6 g, 4.5 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.1 mmol) inmethylene chloride (25 mL) at 0° C. The resulting mixture was stirred atroom temperature for 1 h then diluted with methylene chloride, washedwith saturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified via flashchromatography on a silica gel column eluting with 0 to 20% EtOAc inhexanes to give the desired product (1.8 g, 90%). LC-MS calculated forC₁₉H₂₄F₃N₂O₃(M-^(t)Bu+2H)⁺: m/z=385.2; found 385.2.

Step 3:2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]-acetamide

To a solution of tert-butyl4-methyl-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)-amino]methyl}piperidine-1-carboxylate(1.5 g, 3.4 mmol) in methylene chloride (3 mL) was added hydrogenchloride (4M in 1,4-dioxane, 6 mL, 24 mmol). The resulting mixture wasstirred at room temperature for 1 h then concentrated. The residue wasused in the next step without further purification. LC-MS calculated forC₁₈H₂₄F₃N₂O (M+H)⁺: m/z=341.2; found 341.2.

Step 4:1-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

A mixture of methyl 1-formylcyclopropanecarboxylate (Example 31, Step 8:10. mg, 0.08 mmol), acetic acid (3.3 μL, 0.059 mmol) and2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(20.0 mg, 0.0588 mmol) in methylene chloride (0.4 mL) was stirred atroom temperature for 2 h then sodium triacetoxyborohydride (37 mg, 0.18mmol) was added. The resulting mixture was stirred at room temperaturefor 2 h then diluted with methylene chloride, washed with 1 N NaOH,water and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in MeOH/THF (0.5/0.5 mL) andthen NaOH (15 wt % in water, 1.0 mL) was added. The reaction mixture wasstirred at 40° C. overnight then cooled to room temperature and purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₂₁H₃₁N₂O₂ (M+H)⁺: m/z=343.2;found 343.2.

Example 451-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

A mixture of ethyl 1-formylcyclobutanecarboxylate (Example 32, Step 1:27.5 mg, 0.176 mmol), acetic acid (15 μL, 0.26 mmol) and2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 44, Step 3: 90.0 mg, 0.264 mmol) in methylene chloride (2 mL)was stirred at room temperature for 2 h then sodiumtriacetoxyborohydride (110 mg, 0.53 mmol) was added. The resultingmixture was stirred at room temperature for 2 h then diluted withmethylene chloride, washed with 1 N NaOH, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in MeOH/THF (0.5/0.5 mL) then NaOH (15 wt % in water, 1.0 mL)was added. The reaction mixture was stirred at 40° C. for 2 days thencooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₃₃N₂O₂ (M+H)⁺: m/z=357.3; found 357.2. ¹H NMR(500 MHz, DMSO) δ 7.34-7.28 (m, 2H), 7.25-7.20 (m, 1H), 7.20-7.16 (m,2H), 3.49 (s, 2H), 3.30-3.04 (m, 6H), 3.02-2.92 (m, 1H), 2.59-2.51 (m,1H), 2.47-2.34 (m, 2H), 2.19-2.07 (m, 2H), 2.07-1.91 (m, 2H), 1.89-1.73(m, 2H), 1.74-1.61 (m, 2H), 1.63-1.46 (m, 1H), 1.35-1.23 (m, 1H), 1.12(s, 3H).

Example 46(1R,2S)—N-({4-methyl-1-[(1-methyl-1H-pyrazol-3-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

1-Methyl-1H-pyrazole-3-carbonyl chloride (51 mg, 0.35 mmol) was added toa solution of2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 44, Step 3: 60.0 mg, 0.176 mmol) and triethylamine (98 μL, 0.70mmol) in methylene chloride (2 mL) at 0° C. The resulting mixture wasstirred for 30 min then concentrated. The residue was dissolved inmethanol/THF (0.5 mL/0.5 mL) then 1 N NaOH (1.0 mL) was added. Themixture was stirred at 40° C. overnight then cooled to room temperatureand purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₁H₂₉N₄O (M+H)⁺:m/z=353.2; found 353.3. ¹H NMR (500 MHz, DMSO) δ 8.76 (br, 2H), 7.73 (d,J=2.2 Hz, 1H), 7.35-7.26 (m, 2H), 7.25-7.12 (m, 3H), 6.49 (d, J=2.2 Hz,1H), 4.26-4.10 (m, 1H), 4.03-3.88 (m, 1H), 3.86 (s, 3H), 3.67-3.51 (m,1H), 3.38-3.21 (m, 1H), 3.15-3.06 (m, 2H), 3.04-2.94 (m, 1H), 2.56-2.50(m, 1H), 1.59-1.48 (m, 3H), 1.46-1.34 (m, 2H), 1.32-1.24 (m, 1H), 1.11(s, 3H).

Example 47(1R,2S)—N-({4-methyl-1-[(1-methyl-1H-imidazol-4-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

Triethylamine (31 μL, 0.22 mmol) was added to a solution of1-methyl-1H-imidazole-4-carboxylic acid (Combi-Blocks, cat#HI-1090: 11mg, 0.088 mmol),2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 44, Step 3: 15 mg, 0.044 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (46mg, 0.088 mmol) in N,N-dimethylformamide (0.8 mL). The resulting mixturewas stirred at room temperature for 4 h then NaOH (15 wt % in water, 0.5mL) was added. The reaction mixture was stirred at 40° C. overnight thencooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₂₉N₄O (M+H)⁺: m/z=353.2; found 353.2.

Example 485-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyrimidin-2-amine

This compound was prepared using procedures analogous to those describedfor Example 47 with 2-aminopyrimidine-5-carboxylic acid (Ark Pharm,cat#AK-17303) replacing 1-methyl-1H-imidazole-4-carboxylic acid. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₂₈N₅O (M+H)⁺: m/z=366.2; found 366.2.

Example 496-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyridazin-3-amine

This compound was prepared using procedures analogous to those describedfor Example 47 with 6-aminopyridazine-3-carboxylic acid (Chem-Impex,cat#19168) replacing 1-methyl-1H-imidazole-4-carboxylic acid. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₂₈N₅O (M+H)⁺: m/z=366.2; found 366.3.

Example 504-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-3-amine

This compound was prepared using procedures analogous to those describedfor Example 47 with 3-amino-1H-pyrazole-4-carboxylic acid (Aldrich,cat#A77407) replacing 1-methyl-1H-imidazole-4-carboxylic acid. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₀H₂₈N₅O (M+H)⁺: m/z=354.2; found 354.2.

Example 511-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclopentanamine

Triethylamine (120 μL, 0.88 mmol) was added to a solution of1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (Fluka,cat#03583: 50. mg, 0.22 mmol),2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 44, Step 3: 60. mg, 0.17 mmol) and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (140mg, 0.26 mmol) in N,N-dimethylformamide (2 mL). The resulting mixturewas stirred at room temperature for 1 h then diluted with ethyl acetate,washed with saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was dissolvedin CH₂Cl₂ (0.3 mL) and then TFA (0.3 mL) was added. The mixture wasstirred at room temperature for 1 h then concentrated and the residuewas dissolved in THF/MeOH (0.2 mL/0.2 mL) and then NaOH (15 wt % inwater, 0.5 mL) was added. The mixture was stirred at 35° C. overnightthen cooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₃₄N₃O (M+H)⁺: m/z=356.3; found 356.3. ¹H NMR(500 MHz, DMSO) δ 8.83 (br, 2H), 8.09 (br, 3H), 7.34-7.27 (m, 2H),7.26-7.19 (m, 1H), 7.19-7.14 (m, 2H), 3.82-3.45 (m, 2H), 3.38-3.23 (m,2H), 3.17-3.05 (m, 2H), 3.04-2.93 (m, 1H), 2.57-2.50 (m, 1H), 2.20-2.03(m, 2H), 2.01-1.80 (m, 6H), 1.62-1.46 (m, 3H), 1.45-1.35 (m, 2H),1.34-1.25 (m, 1H), 1.10 (s, 3H).

Example 525-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}pyrimidin-2-amine

A mixture of2,2,2-trifluoro-N-[(4-methylpiperidin-4-yl)methyl]-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 44, Step 3: 15.0 mg, 0.0441 mmol) and2-aminopyrimidine-5-carbaldehyde (Matrix Scientific, cat#008626: 11 mg,0.092 mmol) in methylene chloride (0.5 mL) was stirred at roomtemperature for 1 h then sodium triacetoxyborohydride (28 mg, 0.13 mmol)was added. The resulting mixture was stirred at room temperature for 4 hthen concentrated. The residue was dissolved in methanol/THF (0.4/0.4mL) then NaOH (15 wt % in water, 1.5 mL) was added. The mixture wasstirred at 40° C. overnight then cooled to room temperature and purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₂₁H₃₀N₅(M+H)⁺: m/z=352.2; found352.3.

Example 531-{[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: 1-tert-butyl 4-methyl4-[4-(cyanomethyl)benzyl]piperidine-1,4-dicarboxylate

To a solution of N,N-diisopropylamine (1.59 mL, 11.3 mmol) intetrahydrofuran (55 mL) at −78° C. was added 2.5 M n-butyllithium inhexanes (4.35 mL, 10.9 mmol). This solution was warmed and stirred at 0°C. for 30 min then cooled to −78° C., and added another solution of1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (2.75 g, 11.3 mmol)in tetrahydrofuran (5.0 mL). The resulting solution was stirred at −45°C. for 1 h, and cooled back to −78° C. before another solution of[4-(chloromethyl)phenyl]acetonitrile (Enamine LTD, cat#EN300-134377:1.50 g, 9.06 mmol) in tetrahydrofuran (5.0 mL) was added. The reactionmixture was stirred at −78° C. for 1.5 h, quenched with saturated NaHCO₃solution, and diluted with EtOAc. The organic layer was separated,washed with brine, dried over Na₂SO₄, and concentrated. The crudematerial was purified via column chromatography (25% to 75% EtOAc inhexanes) to give the product (1.31 g, 39%) as a colorless oil. LC-MScalculated for C₁₇H₂₁N₂O₄ (M-^(t)Bu+2H)⁺: m/z=317.1; found 317.2.

Step 2: tert-butyl4-[4-(cyanomethyl)benzyl]-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl4-[4-(cyanomethyl)benzyl]piperidine-1,4-dicarboxylate (1.04 g, 2.79mmol) in tetrahydrofuran (20 mL) at room temperature was added 2.0 Mlithium tetrahydroborate in THF (2.8 mL, 5.6 mmol). The reaction mixturewas then stirred at 65° C. for 2 days, cooled to room temperature, andquenched with a saturated NaHCO₃ solution. This mixture was extractedwith EtOAc, and the combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated. The crude material was purified viacolumn chromatography (0% to 15% MeOH in DCM) to give the product (862mg, 90%) as a colorless oil. LC-MS calculated for C₁₆H₂₁N₂O₃(M-^(t)Bu+2H)⁺: m/z=289.2; found 289.1.

Step 3: tert-butyl4-[4-(cyanomethyl)benzyl]-4-formylpiperidine-1-carboxylate

To a solution of oxalyl chloride (0.42 mL, 5.0 mmol) in methylenechloride (15 mL) at −78° C. was first added dimethyl sulfoxide (0.71 mL,10. mmol) dropwise. The resulting solution was stirred at −78° C. for 30min, and then added another solution of tert-butyl4-[4-(cyanomethyl)benzyl]-4-(hydroxymethyl)piperidine-1-carboxylate(862.8 mg, 2.505 mmol) in methylene chloride (5.0 mL). The reactionmixture was stirred, and warmed to −40° C. for over 1 h, andN,N-diisopropylethylamine (2.6 mL, 15 mmol) was added. This mixture wasfurther stirred and warmed to 0° C. over 1 h, and then diluted with DCM,and poured into 1 M HCl. The organic layer was separated, dried overNa₂SO₄, and concentrated. The resulting residue was purified via columnchromatography (0% to 50% EtOAc in hexanes) to give the product (715 mg,84%) as a colorless oil. LC-MS calculated for C₁₆H₁₉N₂O₃ (M-^(t)Bu+2H)⁺:m/z=287.1; found 287.2.

Step 4: tert-butyl4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl-)piperidine-1-carboxylate

A mixture of tert-butyl4-[4-(cyanomethyl)benzyl]-4-formylpiperidine-1-carboxylate (715 mg,2.087 mmol), acetic acid (178 μL, 3.13 mmol), and(1R,2S)-2-phenylcyclopropanamine (361 mg, 2.71 mmol) in1,2-dichloroethane (12 mL) was stirred at room temperature for 2 h, andthen sodium triacetoxyborohydride (880 mg, 4.2 mmol) was added. Thereaction mixture was stirred at room temperature overnight then quenchedwith saturated NaHCO₃ solution, and diluted with DCM. The organic layerwas separated, washed with brine, dried over Na₂SO₄, and concentrated.The crude material was purified via column chromatography (0% to 30%EtOAc in DCM) to give the product (659 mg, 69%) as colorless oil. LC-MScalculated for C₂₉H₃₈N₃O₂ (M+H)⁺: m/z=460.3; found 460.3.

Step 5: tert-butyl4-[4-(cyanomethyl)benzyl]-4-{[[(1R,2S)-2-phenylcyclopropyl]-(trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

To a solution of tert-butyl4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(659 mg, 1.43 mmol) and N,N-diisopropylethylamine (0.75 mL, 4.3 mmol) inmethylene chloride (13 mL) at 0° C. was added trifluoroacetic anhydride(0.31 mL, 2.2 mmol). The reaction mixture was stirred and slowly warmedto room temperature over 2 h. The resulting mixture was quenched withsaturated NaHCO₃ solution, and diluted with DCM. The organic layer wasseparated, dried over Na₂SO₄, and concentrated. The crude material waspurified via column chromatography (25% to 75% EtOAc in hexanes) to givethe product (760 mg, 95%) as a slightly yellow oil. LC-MS calculated forC₂₇H₂₉F₃N₃O₃(M-^(t)Bu+2H)⁺: m/z=500.2; found 500.2.

Step 6:N-({4-[4-(cyanomethyl)benzyl]piperidin-4-yl}methyl)-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamidehydrochloride

To a solution of tert-butyl4-[4-(cyanomethyl)benzyl]-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate(760. mg, 1.37 mmol) in methylene chloride (10 mL) at 0° C. was added4.0 M hydrogen chloride in 1,4-dioxane (1.7 mL, 6.8 mmol). The reactionmixture was then stirred at room temperature for 1.5 h then concentratedto give the crude product as a slightly yellow solid (HCl salt) whichwas used in the next step without further purification. LC-MS calculatedfor C₂₆H₂₉F₃N₃O (M+H)⁺: m/z=456.2; found 456.2.

Step 7: 1-tert-butyl 1-methyl cyclopropane-1,1-dicarboxylate

To a solution of tert-butyl methyl malonate (7.6 g, 44 mmol) inN,N-dimethylformamide (70. mL) was added 1-bromo-2-chloro-ethane (7.2mL, 87 mmol), potassium carbonate (15 g, 110 mmol) and1-butyl-3-methyl-1H-imidazol-3-ium tetrafluoroborate (2 g, 9 mmol). Theresulting mixture was stirred at room temperature for 48 h then quenchedwith water and extracted with diethylether. The combined extracts werewashed with water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was used in the next step withoutfurther purification.

Step 8: 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid

To a solution of 1-tert-butyl 1-methyl cyclopropane-1,1-dicarboxylate(8.6 g, 43 mmol) in tetrahydrofuran (60 mL), methanol (30 mL) and water(30 mL) was added lithium hydroxide, monohydrate (3.6 g, 86 mmol). Themixture was stirred at room temperature for 2 h then concentrated toremove most of the solvents. The residue was dissolved in water andextracted with diethylether. The ether extracts were discarded. Theaqueous layer was acidified to pH 2 with cold 6 N HCl aqueous solution,then extract with DCM. The combined extracts were dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the desiredcompound (6.5 g, 81%), which was used in the next step without furtherpurification.

Step 9: tert-butyl 1-(hydroxymethyl)cyclopropanecarboxylate

Isobutyl chloroformate (5.9 mL, 45 mmol) was added to a solution of1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (6.5 g, 35 mmol) andtriethylamine (9.7 mL, 70. mmol) in tetrahydrofuran (80 mL) at 0° C. Theresulting mixture was stirred at 0° C. for 60 min then filtered andwashed with THF (10 mL). The filtrate was cooled to 0° C. and then asolution of sodium tetrahydroborate (2.6 g, 70. mmol) inN-methylpyrrolidinone (10 mL) was added. The reaction mixture wasstirred at room temperature for 2 h then diluted with ether, washed withsaturated NaHCO₃ aqueous solution, water and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting withEtOAc in hexane (0-15%) to give the desired product (4.4 g, 73%). ¹H NMR(300 MHz, CDCl₃) δ 3.56 (s, 2H), 2.39 (br, 1H), 1.44 (s, 9H), 1.23-1.14(m, 2H), 0.84-0.75 (m, 2H).

Step 10: tert-butyl 1-formylcyclopropanecarboxylate

Dimethyl sulfoxide (7.2 mL, 100 mmol) was added to a solution of oxalylchloride (4.32 mL, 51.1 mmol) in methylene chloride (100 mL) at −78° C.over 10 min. The resulting mixture was stirred for 10 min at −78° C.then a solution of tert-butyl 1-(hydroxymethyl)cyclopropanecarboxylate(4.4 g, 26 mmol) in methylene chloride (40 mL) was slowly added. Thereaction mixture was stirred at −78° C. for 1 h thenN,N-diisopropylethylamine (36 mL, 200 mmol) was added and the mixturewas slowly warmed to room temperature. The reaction mixture was pouredinto saturated NaHCO₃ aqueous solution and extracted with DCM. Thecombined extracts were washed with water and brine. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting withEtOAc in hexane (0-10%) to give the desired product (3.1 g, 71%). ¹H NMR(400 MHz, CDCl₃) δ 10.36 (s, 1H), 1.61-1.57 (m, 2H), 1.56-1.51 (m, 2H),1.51 (s, 9H).

Step 11: tert-butyl1-[(4-[4-(cyanomethyl)benzyl]-4-{[[(1R,2S)-2-phenylcyclopropyl]-(trifluoroacetyl)amino]methyl}piperidin-1-yl)methyl]cyclopropanecarboxylate

A mixture ofN-({4-[4-(cyanomethyl)benzyl]piperidin-4-yl}methyl)-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamidehydrochloride (Step 6: 400.0 mg, 0.8130 mmol), tert-butyl1-formylcyclopropanecarboxylate (346 mg, 2.03 mmol), and acetic acid(139 μL, 2.44 mmol) in methylene chloride (7.5 mL) was stirred at roomtemperature for 1.5 h, and then sodium triacetoxyborohydride (431 mg,2.03 mmol) was added. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with saturatedNaHCO₃ aqueous solution, and extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with EtOAc in DCM(0-50%) to give the desired product as a yellow solid. LC-MS calculatedfor C₃₅H₄₃F₃N₃O₃(M+H)⁺: m/z=610.3; found 610.3.

Step 12:1-{[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

The product from Step 11 was dissolved in DCM (6 mL) then TFA (3 mL) wasadded. The reaction mixture was stirred at room temperature for 1.5 hthen concentrated. The residue was dissolved in THF/MeOH (1.0 mL/1.0 mL)then 1 M NaOH (1.5 mL) was added. This mixture was stirred at roomtemperature for 3.5 h then purified via prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₆N₃O₂ (M+H)⁺: m/z=458.3; found 458.2.

Example 541-{[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

A mixture ofN-({4-[4-(cyanomethyl)benzyl]piperidin-4-yl}methyl)-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 53, Step 6: 105 mg, 0.230 mmol), methyl1-formylcyclobutanecarboxylate (Example 32, Step 1: 59.6 μL, 0.461mmol), and acetic acid (39 μL, 0.69 mmol) in methylene chloride (3.5 mL)was stirred at room temperature for 1.5 h, and then sodiumtriacetoxyborohydride (122 mg, 0.576 mmol) was added to the reactionmixture. The resultant reaction mixture was stirred at room temperatureovernight then quenched with saturated NaHCO₃ solution, and extractedwith DCM. The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. The crude material was purified via flashchromatography on a silica gel column (gradient elution, 0 to 5% MeOH inDCM) to give the crude intermediate methyl1-((4-(4-(cyanomethyl)benzyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylateas a yellow oil. The intermediate was dissolved in MeOH/THF (1.5 mL/1.5mL), and then 6 M NaOH (1.5 mL) was added to the reaction mixture. Theresultant reaction mixture was stirred at room temperature for 5 h, thendiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₀H₃₈N₃O₂ (M+H)⁺: m/z=472.3; found 472.3.

Example 551-{[4-(4-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 53 with p-cyanobenzyl bromidereplacing[4-(chloromethyl)phenyl]acetonitrile. The reaction mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₈H₃₄N₃O₂ (M+H)⁺:m/z=444.3; found 444.3.

Example 561-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: tert-butyl4-(3-bromobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

This compound was prepared using similar procedures as described forExample 53, Step 1-5 with 1-bromo-3-(bromomethyl)benzenereplacing[4-(chloromethyl)phenyl]acetonitrile in Step 1. LC-MScalculated for C₂₅H₂₇BrF₃N₂O₃ (M-^(t)Bu+2H)⁺: m/z=539.1; found 539.1.

Step 2: tert-butyl4-(3-cyanobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

A mixture of tert-butyl4-(3-bromobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate(3.57 g, 6.00 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (1.2 g, 1.44 mmol), zinc cyanide (2.25 g,19.2 mmol), and zinc (392 mg, 6.00 mmol) in DMF (25 mL) was purged withnitrogen then stirred at 140° C. for 5 h. The reaction mixture wascooled to room temperature, diluted with Et₂O and washed with water.Layers were separated and the organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on a silica gel column eluting with 20-50% EtOAc/Hexanesto give the desired product (2.24 g, 69% yield). LC-MS calculated forC₂₆H₂₇F₃N₃O₃(M-^(t)Bu+2H)⁺: m/z=486.2; found 486.2.

Step 3: N-{[4-(3-cyanobenzyl)piperidin-4-yl]methyl}-2, 2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

4.0 M Hydrogen chloride in dioxane (3.97 mL, 15.9 mmol) was added to asolution of tert-butyl4-(3-cyanobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}-piperidine-1-carboxylate(1.23 g, 2.27 mmol) in MeOH (5 mL). The resulting solution was stirredat room temperature for 1 h then concentrated under reduced pressure.The residue was used in the next step without further purification.LC-MS calculated for C₂₅H₂₇F₃N₃O (M+H)⁺: m/z=442.2; found 442.2.

Step 4:1-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 53, Step 11-12 starting fromN-{[4-(3-cyanobenzyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₄N₃O₂ (M+H)⁺: m/z=444.3; found 444.3.

Example 571-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 54 starting fromN-{[4-(3-cyanobenzyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 56, Step 3). The reaction mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₉H₃₆N₃O₂ (M+H)⁺: m/z=458.3; found 458.3.

Example 58trans-4-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylicacid

Acetic acid (3.6 μL, 0.063 mmol) was added to a solution ofN-{[4-(3-cyanobenzyl)piperidin-4-yl]methyl}-2,2,2-trifluoro-N-[(1R,2S)-2-phenylcyclopropyl]acetamidehydrochloride (Example 56, Step 3: 15.0 mg, 0.0314 mmol) and methyltrans-4-formylcyclohexanecarboxylate (Ark Pharm, cat#AK-50935: 8.0 mg,0.047 mmol) in DCM (0.5 mL). Then sodium triacetoxyborohydride (13 mg,0.063 mmol) was added to the reaction mixture. The resultant reactionmixture was stirred at room temperature for 2 h, then diluted with DCMand washed with water and brine. Layers were separated and the organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude intermediate methyltrans-4-((4-(3-cyanobenzyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)cyclohexanecarboxylatewas dissolved in MeOH (0.2 mL) and THF (0.2 mL) then 4.0 M sodiumhydroxide in water (78. L, 0.31 mmol) was added to the reaction mixture.The resultant reaction mixture was stirred at room temperature overnightthen diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₁H₄₀N₃O₂ (M+H)⁺: m/z=486.3; found 486.3.

Example 593-{[1-(3-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoicacid

Step 1: tert-butyl4-[3-(methoxycarbonyl)benzyl]-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

A mixture of tert-butyl4-(3-bromobenzyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate(Example 56, Step 1: 399 mg, 0.67 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (82 mg, 0.10 mmol) and triethylamine (0.18mL, 1.34 mmol) in methanol (2.50 mL) was refluxed under the positivepressure of carbon monoxide for 7 h. The resulting mixture was cooled toroom temperature, diluted with DCM then filtered through a pad ofcelite. The filtrate was concentrated in vacuo, and the crude residuewas purified by chromatography on silica gel eluting with 15-35%EtOAc/Hexanes to give the desired product 291 mg (75% yield). LC-MScalculated for C₂₆H₃₀F₃N₂O₃[M-Boc+2H]+: m/z=475.2; found 475.2.

Step 2: methyl3-[(4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidin-4-yl)methyl]benzoate

Hydrogen chloride (3M in MeOH, 1.35 mL, 4.05 mmol) was added to asolution of tert-butyl4-[3-(methoxycarbonyl)benzyl]-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)-amino]methyl}piperidine-1-carboxylate(291 mg, 0.51 mmol) in MeOH (5 mL). The resulting solution was stirredat room temperature for 1 h and then concentrated in vacuo. The cruderesidue was used in the next step without further purification. LC-MScalculated for C₂₆H₃₀F₃N₂O₃ [M+H]+: m/z=475.2; found 475.2.

Step 3:3-{[1-(3-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoicacid

Acetic acid (3.1 μL, 0.055 mmol) was added to a solution of methyl3-[(4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]}methylpiperidin-4-yl)methyl]benzoate (14 mg, 0.027 mmol) and benzaldehyde,3-methoxy- (5.01 μL, 0.0411 mmol) in methylene chloride (0.3 mL). Thensodium triacetoxyborohydride (12 mg, 0.055 mmol) was added to thereaction mixture. The resultant reaction mixture was stirred at roomtemperature for 2 h, then diluted with DCM and washed with water andbrine. Layers were separated and the organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo. The intermediate methyl3-((1-(3-methoxybenzyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-4-yl)methyl)benzoatewas dissolved in MeOH (0.3 mL) and THF (0.3 mL) then 4.0 M Sodiumhydroxide in water (68 μL, 0.27 mmol) was added to the reaction mixture.The resultant reaction mixture was stirred at room temperatureovernight, then diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₁H₃₇N₂O₃ [M+H]+: m/z=485.3; found 485.3.

Example 60(3R)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyrrolidin-3-ol

Step 1: phenyl4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate

Carbonochloridic acid, phenyl ester (45.7 μL, 0.364 mmol) was added to asolution of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 90 mg, 0.24 mmol) and triethylamine (0.10 mL, 0.73mmol) in methylene chloride (1.0 mL) at 0° C. and the resultant reactionmixture was stirred for 1 h. The reaction mixture was diluted with ethylacetate, washed with saturated solution of NaHCO₃, water and brine.Layers were separated and the organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified byflash chromatography on a silica gel column (gradient elution with 0 to30% EtOAc/Hexanes) to give the desired product. LC-MS calculated forC₂₆H₃₀F₃N₂O₄ [M+H]+: m/z=491.2; found 491.2.

Step 2:(3R)-1-{[4-(methoxymethyl)-4-({[(R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyrrolidin-3-ol

(3R)-pyrrolidin-3-ol (16 mg, 0.18 mmol) was added to a solution ofphenyl4-(methoxymethyl)-4-{[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]methyl}piperidine-1-carboxylate(18 mg, 0.037 mmol) and triethylamine (15 μL, 0.11 mmol) in dimethylsulfoxide (0.5 mL). The resulting mixture was stirred at 135° C.overnight, then cooled to room temperature and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired intermediate2,2,2-trifluoro-N-((1-((R)-3-hydroxypyrrolidine-1-carbonyl)-4-(methoxymethyl)piperidin-4-yl)methyl)-N-((1S,2R)-2-phenylcyclopropyl)acetamideas the TFA salt. The intermediate was dissolved in MeOH/THF (0.2 mL/0.2mL) and then 6 N NaOH (0.6 mL) was added. The resulting mixture wasstirred at 30° C. overnight, then cooled to room temperature andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₂H₃₄N₃O₃ [M+H]+:m/z=388.3; found 388.2.

Example 61(3S)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyrrolidin-3-ol

This compound was prepared using similar procedures as described forExample 60 with (3S)-pyrrolidin-3-ol replacing (3R)-pyrrolidin-3-ol inStep 2. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₃₄N₃O₃ [M+H]+: m/z=388.3; found 388.2.

Example 624-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}benzoicacid

A mixture of 4-carbomethoxybenzaldehyde (20 mg, 0.12 mmol), acetic acid(5 μL, 0.088 mmol) and2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 30.0 mg, 0.0810 mmol) in methylene chloride (0.6mL) was stirred at room temperature for 2 h and then sodiumtriacetoxyborohydride (56 mg, 0.26 mmol) was added to the reactionmixture. The resulting reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with methylene chloride,washed with 1N NaOH, water and brine. Layers were separated and theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The crude methyl4-((4-(methoxymethyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoatewas dissolved in MeOH/THF (0.1 mL/0.1 mL) and then 6N NaOH (0.6 mL) wasadded. The reaction mixture was stirred at 40° C. overnight, then cooledto room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₅H₃₃N₂O₃ [M+H]+: m/z=409.2; found 409.3.

Example 631-{[4-({[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

Step 1: [4-(methoxymethyl)piperidin-4-yl]methanol

4.0 M Hydrogen chloride in dioxane (4.0 mL, 16 mmol) was added to asolution of tert-butyl4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate (Example 35,Step 2: 1.0 g, 3.8 mmol) in methylene chloride (0.2 mL). The resultingreaction mixture was stirred at room temperature for 30 min and thenconcentrated in vacuo. The crude residue was used in the next stepwithout further purification. LC-MS calculated for C₈H₁₈NO₂ [M+H]+:m/z=160.1; found 160.2.

Step 2: methyl1-{[4-(hydroxymethyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylate

N,N-Diisopropylethylamine (0.82 mL, 4.71 mmol) was added to a mixture of[4-(methoxymethyl)piperidin-4-yl]methanol (0.50 g, 3.1 mmol) (HCl salt,crude product from Step 1) in methylene chloride (20 mL) then methyl1-formylcyclobutanecarboxylate (0.68 g, 4.8 mmol) was added. Theresulting reaction mixture was stirred at room temperature for 1 h andthen sodium triacetoxyborohydride (2.0 g, 9.4 mmol) was added. Thereaction mixture was stirred at room temperature overnight, then dilutedwith methylene chloride, washed with 1N NaOH, water and brine. Layerswere separated and the organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The product was purified by flash chromatographyon a silica gel column (gradient elution with 0 to 10% MeOH/CH₂Cl₂) togive the desired product. LC-MS calculated for C₁₅H₂₈NO₄ [M+H]+:m/z=286.2; found 286.1.

Step 3: methyl1-{[4-formyl-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylate

Dimethyl sulfoxide (0.28 mL, 4.0 mmol) in methylene chloride (0.4 mL)was added to a solution of oxalyl chloride (0.17 mL, 2.0 mmol) inmethylene chloride (0.4 mL) at −78° C. over 10 min. The mixture waswarmed to −60° C. over 25 min then a solution of methyl1-{[4-(hydroxymethyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylate(0.29 g, 1.0 mmol) in methylene chloride (0.4 mL) was slowly added andthen warmed to −45° C. over 30 min. N,N-Diisopropylethylamine (1.4 mL,7.9 mmol) was then added and the reaction mixture was warmed to 0° C.over 15 min. The reaction mixture was poured into cold water andextracted with methylene chloride. The combined extracts were dried overNa₂SO₄, filtered and concentrated in vacuo. The product was purified byflash chromatography on a silica gel column (dragient elution with 0 to10% MeOH/CH₂Cl₂) to give the desired product. LC-MS calculated forC₁₅H₂₆NO₄ [M+H]+: m/z=284.2; found 284.2.

Step 4:1-{[4-({[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

N,N-Diisopropylethylamine (35 μL, 0.20 mmol) was added to a mixture of(1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride (Enamine,cat#EN300-189082: 19 mg, 0.10 mmol) in methylene chloride (0.7 mL),followed by the addition of methyl1-{[4-formyl-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylate(42 mg, 0.15 mmol). The resulting mixture was stirred at roomtemperature for 1 h, then sodium triacetoxyborohydride (69 mg, 0.33mmol) was added. The mixture was stirred at room temperature overnightthen diluted with methylene chloride, washed with 1N NaOH, water andbrine. Layers were separated and the organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The intermediate methyl1-((4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-4-(methoxymethyl)piperidin-1-yl)methyl)cyclobutanecarboxylatewas dissolved in MeOH/THF (0.1 mL/0.2 mL) then 6N NaOH (0.5 mL) wasadded. The mixture was stirred at 30° C. overnight, cooled to roomtemperature and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₂₃H₃₄FN₂O₃ [M+H]+: m/z=405.3; found 405.2.

Example 641-{[4-({[(1R,2S)-2-(2-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 63 with (1R,2S)-2-(2-fluorophenyl)cyclopropanamine hydrochloride(Enamine, cat#EN300-189085) replacing(1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₃₄FN₂O₃ [M+H]+: m/z=405.3; found 405.3.

Example 651-{[4-({[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 63 with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminehydrochloride (AstaTech, cat65978) replacing(1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₃₃F₂N₂O₃ [M+H]+: m/z=423.2; found 423.2.

Example 661-{[4-(methoxymethyl)-4-({[2-(2-methoxyphenyl)cyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 63 with 2-(2-methoxyphenyl)cyclopropanamine hydrochloride(Enamine, cat#EN300-70572) replacing(1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₇N₂O₄ [M+H]+: m/z=417.3; found 417.3.

Example 671-{[4-(methoxymethyl)-4-({[2-(4-methoxyphenyl)cyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 63 with 2-(4-methoxyphenyl)cyclopropanamine hydrochloride(Enamine, cat#EN300-72215) replacing(1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride in Step 4. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₇N₂O₄ [M+H]⁺: m/z=417.3; found 417.2.

Example 681-{[4-(methoxymethyl)-4-(1-{[(1R,2S)-2-phenylcyclopropyl]amino}ethyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

Step 1: tert-butyl4-(methoxymethyl)-4-{[methoxy(methyl)amino]carbonyl}piperidine-1-carboxylate

2.0 M Isopropylmagnesium chloride in THF (3.0 mL, 6.0 mmol) was added toa mixture of 1-tert-butyl 4-methyl4-(methoxymethyl)piperidine-1,4-dicarboxylate (Example 35, Step 1: 0.86g, 3.0 mmol) and N,O-Dimethylhydroxylamine hydrochloride (0.44 g, 4.5mmol) in tetrahydrofuran (12 mL) at −30° C. The resulting mixture waswarmed to 0° C. and stirred at that temperature for 4 h. The mixture wasdiluted with ethyl acetate, washed with saturated NaHCO₃, water andbrine. Layers were separated and the organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The product was purified byflash chromatography on a silica gel column (gradient elution with 0 to30% EtOAc/CH₂Cl₂) to give the desired product (0.8 g, 84%). LC-MScalculated for C₁₀H₂₁N₂O₃ [M-Boc+2H]⁺: m/z=217.2; found 217.2.

Step 2: tert-butyl 4-acetyl-4-(methoxymethyl)piperidine-1-carboxylate

Methylmagnesium bromide (3.0 M in diethyl ether, 2.0 mL, 6.0 mmol) wasadded to a solution of tert-butyl4-(methoxymethyl)-4-{[methoxy(methyl)amino]carbonyl}piperidine-1-carboxylate(0.95 g, 3.0 mmol) in tetrahydrofuran (10 mL) at 0° C. The mixture waswarmed to room temperature and stirred for 5 h. The mixture was quenchedwith saturated solution of NH₄Cl, diluted with ethyl acetate, washedwith water and brine. Layers were separated and the organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by flash chromatography (gradient elution with 0 to 30%EtOAc/Hexane) to give the desired product (0.65 g, 80%). LC-MScalculated for C₉H₁₈NO₂ [M-Boc+2H]⁺: m/z=172.1; found 172.1.

Step 3: tert-butyl4-(methoxymethyl)-4-(1-{[(1R,2S)-2-phenylcyclopropyl]amino}ethyl)piperidine-1-carboxylate

A mixture of tert-butyl4-acetyl-4-(methoxymethyl)piperidine-1-carboxylate (0.27 g, 1.0 mmol),acetic acid (85 μL, 1.5 mmol) and (1R,2S)-2-phenylcyclopropanamine(0.173 g, 1.30 mmol) in methylene chloride (4 mL) was stirred at roomtemperature for 2 h, then sodium triacetoxyborohydride (0.64 g, 3.0mmol) was added to the reaction mixture. The resulting reaction mixturewas stirred at room temperature overnight, then diluted with methylenechloride, washed with saturated solution of NaHCO₃, water and brine.Layers were separated and the organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography (gradient elution with 0 to 8% MeOH/CH₂Cl₂) to give thedesired product. LC-MS calculated for C₂₃H₃₇N₂O₃ [M+H]⁺: m/z=389.3;found 389.3.

Step 4: tert-butyl4-(methoxymethyl)-4-{1-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]ethyl}piperidine-1-carboxylate

Trifluoroacetic anhydride (0.065 mL, 0.46 mmol) was added to a solutionof tert-butyl4-(methoxymethyl)-4-(1-{[(1R,2S)-2-phenylcyclopropyl]amino}ethyl)piperidine-1-carboxylate(120 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.93 mmol)in methylene chloride (3.0 mL) at 0° C. The resulting reaction mixturewas stirred at room temperature for 1 h, then diluted with methylenechloride, washed with saturated solution of NaHCO3, water and brine.Layers were separated and the organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude residue was purified byflash chromatography on a silica gel column (gradient elution with 0 to20% EtOAc/Hexane) to give the desired product. LC-MS calculated forC₂₀H₂₈F₃N₂O₂[M-Boc+2H]⁺: m/z=385.2; found 385.1.

Step 5:2,2,2-trifluoro-N-{1-[4-(methoxymethyl)piperidin-4-yl]ethyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

4.0 M Hydrogen chloride in dioxane (0.5 mL, 2 mmol) was added to asolution of tert-butyl4-(methoxymethyl)-4-{1-[[(1R,2S)-2-phenylcyclopropyl](trifluoroacetyl)amino]ethyl}piperidine-1-carboxylate(80.0 mg, 0.165 mmol) in methylene chloride (0.4 mL). The resultantreaction mixture was stirred at room temperature for 30 min and thenconcentrated under reduced pressure. The crude residue was used in thenext step without further purification. LC-MS calculated forC₂₀H₂₈F₃N₂O₂ [M+H]⁺: m/z=385.2; found 385.1.

Step 6:1-{[4-(methoxymethyl)-4-(1-{[(1R,2S)-2-phenylcyclopropyl]amino}ethyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

Methyl 1-formylcyclobutanecarboxylate (Example 32, Step 1: 22 mg, 0.16mmol) was added to a mixture of2,2,2-trifluoro-N-{1-[4-(methoxymethyl)piperidin-4-yl]ethyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(40.0 mg, 0.104 mmol) and N,N-Diisopropylethylamine (27 μL, 0.16 mmol)in methylene chloride (0.8 mL). The resulting mixture was stirred atroom temperature for 2 h then sodium triacetoxyborohydride (72 mg, 0.34mmol) was added. The mixture was stirred at room temperature overnight,then diluted with methylene chloride, washed with 1N NaOH, water andbrine. Layers were separated and the organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The crude intermediatemethyl1-((4-(methoxymethyl)-4-(1-(2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)ethyl)-piperidin-1-yl)methyl)cyclobutanecarboxylatewas dissolved in MeOH/THF (0.2 mL/0.2 mL) and then 6N NaOH (0.6 mL) wasadded to the reaction mixture. The resultant reaction mixture wasstirred at 40° C. for 2 days, then cooled to room temperature andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₄H₃₇N₂O₃ [M+H]⁺:m/z=401.3; found 401.2.

Example 691-{[4-[(6-methoxypyridin-3-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: tert-butyl4-[(6-chloropyridin-3-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

This compound was prepared using similar procedures as described forExample 31, Step 1-4 with 2-chloro-5-(chloromethyl)pyridine (Aldrich,cat#516910) replacing α-bromo-4-fluorotoluene in Step 1. LC-MScalculated for C₂₆H₃₅ClN₃O₂ [M+H]⁺: m/z=456.2; found 456.2.

Step 2: tert-butyl4-({[(allyloxy)carbonyl][(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-[(6-chloropyridin-3-yl)methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[(6-chloropyridin-3-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(1.1 g, 2.4 mmol) in methylene chloride (10 mL) was added allylchloroformate (0.38 mL, 3.6 mmol) and N,N-diisopropylethylamine (0.84mL, 4.8 mmol). The resulting solution was stirred at room temperaturefor 1 h and then concentrated in vacuo. The crude residue was purifiedby flash chromatography on a silica gel column (gradient elution with 0to 30% EtOAc in hexanes) to afford the desired product. LC-MS calculatedfor C₂₆H₃₁ClN₃O₄[M-^(t)Bu+2H]⁺: m/z=484.2; found 484.2.

Step 3: allyl({4-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamate

A mixture of tert-butyl4-({[(allyloxy)carbonyl][(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-[(6-chloropyridin-3-yl)methyl]piperidine-1-carboxylate(350 mg, 0.65 mmol) and sodium methoxide (25 wt % in MeOH, 1.48 mL, 6.48mmol) in methanol (0.5 mL) was stirred at 80° C. for 6 h. The reactionmixture was cooled to room temperature, then diluted with DCM, washedwith water and brine. Layers were separated and the organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography on a silica gel column (gradientelution with 0 to 30% EtOAc in hexanes) to afford the desiredintermediate tert-butyl4-((((allyloxy)carbonyl)((1R,2S)-2-phenylcyclopropyl)amino)methyl)-4-((6-methoxypyridin-3-yl)methyl)piperidine-1-carboxylate.The intermediate was dissolved in DCM (2 mL) then TFA (2 mL) was added.The resulting reaction mixture was stirred at room temperature for 2 h,then concentrated and the crude title product was used in the next stepwithout further purification. LC-MS calculated for C₂₆H₃₄N₃O₃ [M+H]⁺:m/z=436.3; found 436.2.

Step 4:1-{[4-[(6-methoxypyridin-3-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

A mixture of tert-butyl 1-formylcyclopropanecarboxylate (Example 53,Step 10: 18 mg, 0.10 mmol), triethylamine (19 μL, 0.14 mmol) and allyl({4-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamate(30 mg, 0.069 mmol) in methylene chloride (0.8 mL) was stirred at roomtemperature for 1 h then sodium triacetoxyborohydride (29 mg, 0.14 mmol)was added. The resulting mixture was stirred at room temperatureovernight, then diluted with methylene chloride, washed with saturatedsolution of NaHCO₃, water and brine. Layers were separated and theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was dissolved in THF (2 mL) thentetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) andN-ethylethanamine (56 μL, 0.54 mmol) were added. The mixture was purgedwith nitrogen then stirred at 85° C. for 2 h. The reaction mixture wascooled to room temperature, filtered and concentrated in vacuo to yieldintermediate tert-butyl1-((4-((6-methoxypyridin-3-yl)methyl)-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclopropanecarboxylate,which was used further without purification. The intermediate wasdissolved in DCM (1 mL), then TFA (1 mL) was added. The mixture wasstirred at room temperature for 3 h, then concentrated in vacuo and theresidue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₂₇H₃₆N₃O₃[M+H]⁺: m/z=450.3; found 450.2.

Example 701-{[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 35 with (chloromethoxy)-ethane replacing chloromethyl methylether in Step 1. The reaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₃₅N₂O₃ [M+H]⁺: m/z=387.3; found 387.2.

Example 711-{[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 36 with (chloromethoxy)-ethane replacing chloromethyl methylether. The reaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₇N₂O₃ [M+H]⁺: m/z=401.3; found 401.2.

Example 721-{[4-[(benzyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 31 with benzyl chloromethyl ether replacingα-bromo-4-fluorotoluene in Step 1. The mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₈H₃₇N₂O₃ [M+H]⁺: m/z=449.3; found449.3.

Example 731-{[4-[(benzyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 32 with benzyl chloromethyl ether replacingα-bromo-4-fluorotoluene. The mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₉N₂O₃ [M+H]⁺: m/z=463.3; found 463.3.

Example 741-{[4-(4-cyano-2-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 53 with 4-(bromomethyl)-3-fluorobenzonitrile (AstaTech,cat#54500) replacing [4-(chloromethyl)phenyl]acetonitrile in Step 1. Thereaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₃FN₃O₂ [M+H]⁺: m/z=462.3; found 462.3.

Example 751-{[4-[(2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: 1-tert-butyl 4-methyl4-[(benzyloxy)methyl]piperidine-1,4-dicarboxylate

This compound was prepared using similar procedures as described forExample 31, Step 1 with benzyl chloromethyl ether replacingα-bromo-4-fluorotoluene. LC-MS calculated for C₁₅H₂₂NO₃ [M-Boc+2H]⁺:m/z=264.2; found 264.2.

Step 2: 1-tert-butyl 4-methyl4-(hydroxymethyl)piperidine-1,4-dicarboxylate

Palladium (10 wt % on carbon, 880 mg, 0.83 mmol) was added to a solutionof 1-tert-butyl 4-methyl4-[(benzyloxy)methyl]piperidine-1,4-dicarboxylate (2.1 g, 5.8 mmol) inmethanol (20 mL). The resulting reaction mixture was stirred under apositive preassure of hydrogen at room temperature overnight, thenfiltered through celite and washed with DCM. The filtrate wasconcentrated in vacuo and the residue was used in the next step withoutfurther purification. LC-MS calculated for C₈H₁₆NO₃ [M-Boc+2H]⁺:m/z=174.1; found 174.2.

Step 3: 1-tert-butyl 4-methyl4-[(2-fluorophenoxy)methyl]piperidine-1,4-dicarboxylate

To a solution of 1-tert-butyl 4-methyl4-(hydroxymethyl)piperidine-1,4-dicarboxylate (555 mg, 2.03 mmol),2-fluoro-phenol (Aldrich, cat#F12804) (0.16 mL, 1.8 mmol) andtriphenylphosphine (530 mg, 2.0 mmol) in tetrahydrofuran (4 mL) wasadded diisopropyl azodicarboxylate (0.40 mL, 2.0 mmol). The resultingreaction mixture was heated to 65° C. and stirred overnight. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was purified by chromatography on a silica gel column(gradient elution with 0 to 25% EtOAc/Hexanes) to give the desiredproduct as a clear oil (524 mg, 77%). LC-MS calculated for C₁₄H₁₉FNO₃[M-Boc+2H]⁺: m/z=268.1; found 268.2.

Step 4: tert-butyl4-[(2-fluorophenoxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl4-[(2-fluorophenoxy)methyl]piperidine-1,4-dicarboxylate (524 mg, 1.43mmol) in tetrahydrofuran (1.5 mL) was added 2.0 M lithiumtetrahydroborate in THF (1.4 mL, 2.8 mmol). The resulting reactionmixture was heated to 70° C. and stirred for 6 h. The reaction mixturewas cooled to room temperature, quenched with water, diluted with EtOAc,and the organic phase was washed with water and brine. Layers wereseparated and the organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₁₃H₁₉FNO₂ [M-Boc+2H]⁺:m/z=240.1; found 240.2.

Step 5: 2, 2,2-trifluoro-N-({4-[(2-fluorophenoxy)methyl]piperidin-4-yl}methyl)-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

This compound was prepared using similar procedures as described forExample 31, Step 3-6 with tert-butyl4-[(2-fluorophenoxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate(from Step 4) replacing tert-butyl4-(4-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate in Step 3.LC-MS calculated for C₂₄H₂₇F₄N₂₀₂ [M+H]⁺: m/z=451.2; found 451.3.

Step 6:1-{[4-[(2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

To a solution of2,2,2-trifluoro-N-({4-[(2-fluorophenoxy)methyl]piperidin-4-yl}methyl)-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(31 mg, 0.069 mmol) and tert-butyl 1-formylcyclopropanecarboxylate(Example 53, Step 10: 18 mg, 0.10 mmol) in methylene chloride (0.5 mL)was added acetic acid (4.3 μL, 0.075 mmol). The resultant solution wasstirred at room temperature for 2 h, followed by the addition of sodiumtriacetoxyborohydride (48 mg, 0.23 mmol) to the reaction mixture. Thereaction mixture was stirred at room temperature overnight, then dilutedwith DCM, washed with saturated NaHCO₃ solution, water and brine. Layerswere separated and the organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude tert-butyl1-((4-((2-fluorophenoxy)methyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)cyclopropanecarboxylatewas dissolved in DCM (2 mL), then trifluoroacetic acid (0.62 mL) wasadded. The reaction mixture was stirred at room temperature for 1.5 hand then concentrated in vacuo. The crude1-((4-((2-fluorophenoxy)methyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)-piperidin-1-yl)methyl)cyclopropanecarboxylicacid was dissolved in MeOH/THF (0.5/0.5 mL) and then 1N NaOH (0.75 mL)was added. The resulting reaction mixture was stirred at 50° C. for 4 h,then cooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₃₄FN₂O₃ [M+H]⁺: m/z=453.3; found 453.2.

Example 761-{[4-[(2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

To a solution of2,2,2-trifluoro-N-({4-[(2-fluorophenoxy)methyl]piperidin-4-yl}methyl)-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 75, Step 5: 35 mg, 0.077 mmol) and methyl1-formylcyclobutanecarboxylate (Example 32, Step 1: 16 mg, 0.12 mmol) inmethylene chloride (0.6 mL) was added acetic acid (4.7 μL, 0.083 mmol).The reaction mixture was stirred at room temperature for 2 h and thensodium triacetoxyborohydride (53 mg, 0.25 mmol) was added. The resultantreaction mixture was stirred at room temperature overnight, then dilutedwith DCM, washed with saturated NaHCO₃ solution, water and brine. Layerswere separated and the organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude methyl1-((4-((2-fluorophenoxy)methyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylatewas dissolved in MeOH (0.5 mL) and THF (0.5 mL) then 6 N NaOH (0.5 mL)was added. The resulting reaction mixture was stirred at 40° C.overnight, then cooled to room temperature and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₈H₃₆FN₂O₃ [M+H]⁺: m/z=467.3; found 467.3.

Example 771-{[4-[(3-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 75 (using 3-fluoro-phenol (Aldrich, cat#F13002) to replace2-fluoro-phenol in Step 3). The mixture was purified with prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₇H₃₄FN₂O₃ [M+H]⁺: m/z=453.3; found 453.2.

Example 781-{[4-[(3-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 76 and Example 75 (using 3-fluoro-phenol to replace2-fluoro-phenol in step 3). The mixture was purified with prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₈H₃₆FN₂O₃ [M+H]⁺: m/z=467.3; found 467.3.

Example 791-{([4-[(2-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 75 using 2-hydroxybenzonitrile (Aldrich, cat#141038) to replace2-fluoro-phenol in Step 3. The mixture was purified with prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₈H₃₄N₃O₃ [M+H]⁺: m/z=460.3; found 460.3.

Example 801-{[4-[(3-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 75 using 3-hydroxybenzonitrile (Aldrich, cat#C93800) to replace2-fluoro-phenol in Step 3. The mixture was purified with prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₈H₃₄N₃O₃ [M+H]⁺: m/z=460.3; found 460.3.

Example 811-{[4-[(4-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 75 using 4-hydroxybenzonitrile (Aldrich, cat#C94009) to replace2-fluoro-phenol in Step 3. The mixture was purified with prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₈H₃₄N₃O₃ [M+H]⁺: m/z=460.3; found 460.2.

Example 821-{[4-[(4-cyano-2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 75 using 3-fluoro-4-hydroxybenzonitrile (Oakwood, cat#013830) toreplace 2-fluoro-phenol in Step 3. The mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₈H₃₃FN₃O₃ [M+H]⁺: m/z=478.3; found478.2.

Example 831-{([4-[(2-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 76 and Example 75 (using 2-cyanophenol (Aldrich, cat#141038) toreplace 2-fluoro-phenol in Step 3). The mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₉H₃₆N₃O₃ [M+H]⁺: m/z=474.3; found474.3.

Example 841-{([4-[(3-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 76 and Example 75 (using 3-cyanophenol (Aldrich, cat#C93800) toreplace 2-fluoro-phenol in Step 3). The mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₉H₃₆N₃O₃ [M+H]⁺: m/z=474.3; found474.3.

Example 851-{[4-[(4-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 76 and Example 75 (using 4-cyanophenol (Aldrich, cat#C94009) toreplace 2-fluoro-phenol in Step 3). The mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₉H₃₆N₃O₃ [M+H]⁺: m/z=474.3; found474.3.

Example 861-{[4-[(4-cyano-2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 76 and Example 75 (using 3-fluoro-4-hydroxybenzonitrile(Oakwood, cat#013830) to replace 2-fluoro-phenol in Step 3). The mixturewas purified with prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₉H₃₅FN₃O₃[M+H]⁺: m/z=492.3; found 492.3.

Example 871-{[4-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: 1-tert-butyl 4-methyl 4-formylpiperidine-1,4-dicarboxylate

Dimethyl sulfoxide (2.5 mL, 35 mmol) in methylene chloride (17 mL) wasadded to a solution of oxalyl chloride (1.5 mL, 17 mmol) in methylenechloride (17 mL) at −78° C. over 20 min and then the reaction mixturewas warmed to −60° C. over 25 min. 1-tert-Butyl 4-methyl4-(hydroxymethyl)piperidine-1,4-dicarboxylate (Example 75, Step 2: 2.39g, 8.74 mmol) in DCM (30 mL) was slowly added and then the reactionmixture was warmed to −45° C. and stirred at that temperature for 1 h.Triethylamine (9.8 mL, 70. mmol) was added and then the reaction mixturewas warmed to 0° C. over 1 h. The reaction mixture was quenched withsaturated aqueous NaHCO₃, and extracted with DCM. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the desired crude productwhich was used in the next step without further purification. LC-MScalculated for C₈H₁₄NO₃ [M-Boc+2H]⁺: m/z=172.1; found 172.2.

Step 2: 1-tert-butyl 4-methyl4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1,4-dicarboxylate

A mixture of (1R,2S)-2-phenylcyclopropanamine (1.30 g, 9.79 mmol),1-tert-butyl 4-methyl 4-formylpiperidine-1,4-dicarboxylate (2.37 g, 8.74mmol) and acetic acid (2.0 mL, 35 mmol) in methylene chloride (50 mL)was stirred at room temperature for 4 h, then cooled to room temperatureand sodium triacetoxyborohydride (4.1 g, 19 mmol) was added to thereaction mixture. The reaction mixture was stirred at room temperaturefor 2h, then quenched with saturated aqueous NaHCO₃, and extracted withDCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column with(gradient elution with 0 to 5% MeOH in DCM) to afford the desiredproduct. LC-MS calculated for C₂₂H₃₃N₂O₄ [M+H]⁺: m/z=389.2; found 389.1.

Step 3: 1-tert-butyl 4-methyl4-({[(allyloxy)carbonyl][(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1,4-dicarboxylate

Allyl chloroformate (1.4 mL, 13 mmol) was added to a solution of theproduct from Step 2 and triethylamine (3.0 mL, 22 mmol) intetrahydrofuran (30 mL) at 0° C. The reaction mixture was warmed to roomtemperature and stirred at that temperature overnight. The reactionmixture was quenched with sat NaHCO₃ and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column (gradientelution with ethyl acetate in hexanes (0-25%)) to afford the desiredproduct. LC-MS calculated for C₂₁H₂₉N₂O₄ [M-Boc+2H]⁺: m/z=373.2; found373.2.

Step 4: tert-butyl4-({[(allyloxy)carbonyl][(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-(hydroxymethyl)piperidine-1-carboxylate

Lithium tetrahydroaluminate (1M in THF, 4.5 mL, 4.5 mmol) was added to asolution of 1-tert-butyl 4-methyl4-({[(allyloxy)carbonyl][(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1,4-dicarboxylate(2.13 g, 4.51 mmol) in tetrahydrofuran (40 mL) at −78° C. The reactionmixture was warmed to −20° C. and stirred at that temperature for 0.5 h.The mixture was quenched with NaHCO₃ (aq.), and extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column (gradientelution with EA in hexanes (0-40%)) to afford the desired product (1.04g, 52%). LC-MS calculated for C₂₀H₂₉N₂O₃ [M-Boc+2H]⁺: m/z=345.2; found345.2.

Step 5: tert-butyl4-({[(allyloxy)carbonyl][(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-{[(5-fluoropyridin-2-yl)oxy]methyl}piperidine-1-carboxylate

To a solution of tert-butyl4-({[(allyloxy)carbonyl][(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-(hydroxymethyl)piperidine-1-carboxylate(208 mg, 0.468 mmol), 5-fluoropyridin-2-ol (Aldrich, cat#753181) (106mg, 0.936 mmol), and triphenylphosphine (245 mg, 0.936 mmol) in toluene(5 mL) at room temperature was added diisopropyl azodicarboxylate (0.19mL, 0.94 mmol) dropwise. The resulting reaction mixture was stirred at50° C. overnight, then concentrated in vacuo. The crude residue waspurified by flash chromatography on a silica gel column (dragientelution with 0 to 35% EtOAc in hexanes) to afford the desired product(249 mg, 99%). LC-MS calculated for C₂₆H₃₁FN₃O₅[M-^(t)Bu+2H]⁺:m/z=484.2; found 484.2.

Step 6. allyl[(4-{[(5-fluoropyridin-2-yl)oxy]methyl}piperidin-4-yl)methyl][(1R,2S)-2-phenylcyclopropyl]carbamate

The product from Step 5 was dissolved in methylene chloride (2.0 mL)then trifluoroacetic acid (2.0 mL) was added. The resulting reactionmixture was stirred at room temperature for 1 h then concentrated underreduced pressure. The residue was dissolved in DCM, then neutralizedwith saturated aqueous NaHCO₃ solution. The organic layer was washedwith brine then dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was used in the next step without further purification.LC-MS calculated for C₂₅H₃₁FN₃O₃ [M+H]⁺: m/z=440.2; found 440.3.

Step 7:1-{[4-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

To a solution of tert-butyl 1-formylcyclopropanecarboxylate (Example 53,Step 10: 27 mg, 0.16 mmol), and allyl[(4-{[(5-fluoropyridin-2-yl)oxy]methyl}piperidin-4-yl)methyl][(1R,2S)-2-phenylcyclopropyl]carbamate(47 mg, 0.11 mmol) in methylene chloride (1 mL) was added acetic acid(6.6 μL, 0.12 mmol). The reaction mixture was stirred at roomtemperature for 1 h then sodium triacetoxyborohydride (45 mg, 0.21 mmol)was added. The mixture was stirred at room temperature for 2 h, thendiluted with methylene chloride, washed with saturated solution ofNaHCO₃, water and brine. Layers were separated and the organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The crudetert-butyl1-((4-((((allyloxy)carbonyl)((1R,2S)-2-phenylcyclopropyl)amino)methyl)-4-(((5-fluoropyridin-2-yl)oxy)methyl)piperidin-1-yl)methyl)cyclopropanecarboxylatewas dissolved in tetrahydrofuran (2.0 mL),tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) andN-ethylethanamine (0.06 mL, 0.6 mmol) were added. The reaction mixturewas purged with nitrogen, then stirred at 85° C. for 2 h. The reactionmixture was cooled to room temperature, then filtered and concentratedin vacuo. The crude tert-butyl1-((4-(((5-fluoropyridin-2-yl)oxy)methyl)-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclopropanecarboxylatewas dissolved in methylene chloride (1.5 mL) and trifluoroacetic acid(1.5 mL) was added. The reaction mixture was stirred at room temperaturefor 1 h, then concentrated and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₃₃FN₃O₃ [M+H]⁺: m/z=454.3; found 454.2.

Example 881-{[4-{[(5-fluoropyrimidin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 87 with 5-fluoropyrimidin-2-ol (Aldrich, cat#656445) replacing5-fluoropyridin-2-ol in Step 5. The reaction mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₅H₃₂FN₄O₃ [M+H]⁺: m/z=455.2; found455.3.

Example 891-{[4-{[(3-fluoropyridin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 87 with 3-fluoropyridin-2-ol (AstaTech, cat#22417) replacing5-fluoropyridin-2-ol in Step 5. The reaction mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₆H₃₃FN₃O₃ [M+H]⁺: m/z=454.3; found454.2.

Example 901-{[4-[({6-[(methylamino)carbonyl]pyridin-3-yl}oxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 87 with 5-hydroxy-N-methylpicolinamide (AstaTech, cat#24328)replacing 5-fluoropyridin-2-ol in Step 5. The reaction mixture waspurified with prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₈H₃₇N₄O₄ [M+H]⁺:m/z=493.3; found 493.3.

Example 911-{[4-[({6-[(methylamino)carbonyl]pyridin-2-yl}oxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: 6-hydroxy-N-methylpicolinamide

The mixture of methyl 6-hydroxypyridine-2-carboxylate (Aldrich,cat#ANV00114: 412 mg, 2.69 mmol) and methylamine (40 wt % in water, 4.0mL, 36 mmol) was stirred at room temperature for 5 days thenconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₇H₉N₂O₂ [M+H]⁺: m/z=153.1; found153.1.

Step 2.1-{[4-[({6-[(methylamino)carbonyl]pyridin-2-yl}oxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared according to the procedures of Example 87with 6-hydroxy-N-methylpicolinamide (product from Step 1) replacing5-fluoropyridin-2-ol in Step 5. The reaction mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₈H₃₇N₄O₄ [M+H]⁺: m/z=493.3; found493.3.

Example 921-{[4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: tert-butyl4-[(benzyloxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate

Lithium tetrahydroaluminate (1M in THF, 28 mL, 28 mmol) was added to asolution of 1-tert-butyl 4-methyl4-[(benzyloxy)methyl]piperidine-1,4-dicarboxylate (Example 75, Step 1:10.0 g, 27.5 mmol) in tetrahydrofuran (200 mL) at −78° C. The reactionmixture was warmed to −20° C. and stirred at that temperature for 0.5 h.The reaction mixture was quenched with NaHCO₃ (aq.), and extracted withethyl acetate. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column(gradient elution with EtOAc in hexanes (0-40%)) to afford the desiredproduct (4.3 g, 46%). LC-MS calculated for C₁₄H₂₂NO₂ [M-Boc+2H]⁺:m/z=236.2; found 236.1.

Step 2: tert-butyl4-[(benzyloxy)methyl]-4-[(cyclobutylmethoxy)methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-[(benzyloxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g,3.0 mmol) in N,N-dimethylformamide (20 mL) was added NaH (60 wt % inmineral oil, 180 mg, 4.5 mmol), the solution was stirred at roomtemperature for 30 min then (bromomethyl)cyclobutane (Aldrich,cat#441171) (670 μL, 6.0 mmol) was added. The resulting reaction mixturewas stirred at 140° C. for 4 days, then cooled to room temperature andquenched with water and extracted with EtOAc. The combined extracts werewashed with water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on a silica gel column (gradient elution with EtOAc inhexanes (0-20%)) to afford the desired product (130 mg, 11%). LC-MScalculated for C₁₉H₃₀NO₂ [M-Boc+2H]⁺: m/z=304.2; found 304.2.

Step 3: tert-butyl4-[(cyclobutylmethoxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-[(benzyloxy)methyl]-4-[(cyclobutylmethoxy)methyl]piperidine-1-carboxylate(130 mg, 0.32 mmol) in methanol (4 mL) was added palladium on activatedcarbon (10 wt %, 30 mg). The reaction mixture was stirred at roomtemperature for 2 h under a positive pressure of hydrogen, then filteredthrough a pad of celite and concentrated in vacuo. The residue was usedin the next step without further purification. LC-MS calculated forC₁₂H₂₄NO₂ [M-Boc+2H]⁺: m/z=214.2; found 214.2.

Step 4: tert-butyl4-[(cyclobutylmethoxy)methyl]-4-formylpiperidine-1-carboxylate

Dimethyl sulfoxide (140 μL, 1.9 mmol) was added to a solution of oxalylchloride (81 μL, 0.96 mmol) in methylene chloride (1 mL) at −78° C. over5 min and the resulting reaction mixture was stirred for 10 min, then asolution of tert-butyl4-[(cyclobutylmethoxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate(100 mg, 0.32 mmol) in methylene chloride (0.8 mL) was slowly added. Thereaction mixture was stirred at −75° C. for 60 min, thenN,N-diisopropylethylamine (0.67 mL, 3.8 mmol) was added. The reactionmixture was slowly warmed to room temperature, then quenched withsaturated aqueous NaHCO₃ solution and extracted with EtOAc. The combinedextracts were washed with water and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo. The residue was used inthe next step without further purification. LC-MS calculated forC₁₂H₂₂NO₂ [M-Boc+2H]⁺: m/z=212.2; found 212.1.

Step 5: tert-butyl4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate

A mixture of tert-butyl4-[(cyclobutylmethoxy)methyl]-4-formylpiperidine-1-carboxylate (crudeproduct from Step 4: 100 mg, 0.32 mmol), acetic acid (27 μL, 0.48 mmol)and (1R,2S)-2-phenylcyclopropanamine (52 mg, 0.38 mmol) in methylenechloride (4 mL) was stirred at room temperature for 1 hour. Then sodiumtriacetoxyborohydride (140 mg, 0.64 mmol) was added and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas diluted with methylene chloride, washed with saturated solution ofNaHCO₃, 1N NaOH, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was used in thenext step without further purification. LC-MS calculated for C₂₆H₄₁N₂O₃[M+H]⁺: m/z=429.3; found 429.3.

Step 6: allyl({4-[(cyclobutylmethoxy)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamate

To a solution of tert-butyl4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidine-1-carboxylate(140 mg, 0.33 mmol) in methylene chloride (2 mL) was added allylchloroformate (69 μL, 0.65 mmol) and N,N-diisopropylethylamine (0.11 mL,0.65 mmol). The resulting solution was stirred at room temperature for 1h and then concentrated under reduced pressure. The residue was purifiedby chromatography on a silica gel column (gradient elution with EtOAc inhexanes (0-20%)) to afford the desired intermediate (tert-butyl4-((((allyloxy)carbonyl)((1R,2S)-2-phenylcyclopropyl)amino)methyl)-4-((cyclobutylmethoxy)methyl)piperidine-1-carboxylate,150 mg). The intermediate was dissolved in DCM (1 mL) then TFA (1 mL)was added. The resulting mixture was stirred at room temperature for 1 hand then concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₂₅H₃₇N₂O₃ [M+H]⁺: m/z=413.3;found 413.2.

Step 7:1-{[4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

A mixture of tert-butyl 1-formylcyclopropanecarboxylate (12 mg, 0.073mmol), triethylamine (14 μL, 0.097 mmol) and allyl({4-[(cyclobutylmethoxy)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamate(20.0 mg, 0.0485 mmol) in methylene chloride (0.6 mL) was stirred atroom temperature for 1 h then sodium triacetoxyborohydride (20 mg, 0.097mmol) was added. The reaction mixture was stirred at room temperatureovernight, then diluted with methylene chloride, washed with saturatedsolution of NaHCO₃, water and brine. Layers were separated and theorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The crude tert-butyl1-((4-((((allyloxy)carbonyl)((1R,2S)-2-phenylcyclopropyl)amino)methyl)-4-((cyclobutylmethoxy)methyl)piperidin-1-yl)methyl)cyclopropanecarboxylatewas dissolved in THF (2 mL) thentetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) andN-ethylethanamine (56 μL, 0.54 mmol) were added. The resulting reactionmixture was purged with nitrogen then stirred at 85° C. for 2 h. Thereaction mixture was cooled to room temperature, filtered andconcentrated in vacuo. The crude tert-butyl1-((4-((cyclobutylmethoxy)methyl)-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclopropanecarboxylatewas dissolved in DCM (1 mL) then TFA (1 mL) was added. The mixture wasstirred at room temperature for 3 h and then concentrated. The residuewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₆H₃₉N₂O₃ [M+H]⁺:m/z=427.3; found 427.2.

Example 931-{[4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

A mixture of methyl 1-formylcyclobutanecarboxylate (Example 32, Step 1:10 mg, 0.073 mmol), triethylamine (14 μL, 0.097 mmol) and allyl({4-[(cyclobutylmethoxy)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamate(Example 92, Step 6: 20 mg, 0.049 mmol) in methylene chloride (0.6 mL)was stirred at room temperature for 1 h, then sodiumtriacetoxyborohydride (20. mg, 0.097 mmol) was added to the reactionmixture. The reaction mixture was stirred at room temperature overnight,then diluted with methylene chloride, washed with saturated solution ofNaHCO₃, water and brine. Layers were separated and the organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The crude methyl1-((4-((((allyloxy)carbonyl)((1R,2S)-2-phenylcyclopropyl)amino)methyl)-4-((cyclobutylmethoxy)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylatewas dissolved in THF (2 mL) thentetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) andN-ethylethanamine (56 μL, 0.54 mmol) were added. The resulting reactionmixture was purged with nitrogen then stirred at 85° C. for 2 h. Themixture was cooled to room temperature, filtered and concentrated invacuo. The crude methyl1-((4-((cyclobutylmethoxy)methyl)-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclobutanecarboxylatewas dissolved in THF (1 mL) and MeOH (1 mL) then lithium hydroxide,monohydrate (20 mg) in water (0.5 mL) was added to the resultantsolution. The resulting reaction mixture was stirred at 40° C. for 5 h,then cooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₄₁N₂O₃ [M+H]⁺: m/z=441.3; found 441.3.

Example 941-{[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: tert-butyl4-[(benzyloxy)methyl]-4-(phenoxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-[(benzyloxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate (Example53, Step 1: 450 mg, 1.34 mmol), phenol (252 mg, 2.68 mmol), andtriphenylphosphine (704 mg, 2.68 mmol) in toluene (10 mL) at roomtemperature was added diisopropyl azodicarboxylate (560 μL, 2.7 mmol)dropwise. The reaction mixture was stirred at 65° C. overnight, thencooled to room temperature and concentrated under reduced pressure. Theresidue was purified by chromatography on a silica gel column (gradientelution with EtOAc in hexanes (0-20%)) to afford the desired product(530 mg, 96%). LC-MS calculated for C₂₀H₂₆NO₂ [M-Boc+2H]⁺: m/z=312.2;found 312.1.

Step 2: tert-butyl4-[(cyclohexyloxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl4-[(benzyloxy)methyl]-4-(phenoxymethyl)piperidine-1-carboxylate (530 mg,1.3 mmol) in methanol (5 mL) was added palladium (10 wt % on activatedcarbon, 138 mg, 0.13 mmol). The reaction mixture was stirred at roomtemperature for 2h under a positive pressure of hydrogen, then filteredthrough a pad of celite and concentrated under reduced pressure. Thecrude tert-butyl4-(hydroxymethyl)-4-(phenoxymethyl)piperidine-1-carboxylate wasdissolved in MeOH (20 mL), then rhodium (5 wt % on activated carbon, 535mg, 0.26 mmol) was added to the resultant solution. The resultingreaction mixture was stirred at room temperature under 45 psi hydrogenfor 3 days. The mixture was filtered through a pad of celite andconcentrated under reduced pressure. The crude title product of step 2was used in the next step without further purification. LC-MS calculatedfor C₁₄H₂₆NO₄ [M-^(t)Bu+2H]⁺: m/z=272.2; found 272.1.

Step 3:1-{[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 92, Step 4-7 starting from tert-butyl4-[(cyclohexyloxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate. Thereaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₄₁N₂O₃ [M+H]⁺: m/z=441.3; found 441.3.

Example 951-{[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

Step 1: allyl({4-[(cyclohexyloxy)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamate

This compound was prepared using similar procedures as described forExample 92, Step 4-6 starting from tert-butyl4-[(cyclohexyloxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate(Example 94, Step 2) instead of tert-butyl4-[(cyclobutylmethoxy)methyl]-4-(hydroxymethyl)piperidine-1-carboxylate.LC-MS calculated for C₂₆H₃₉N₂O₃ [M+H]⁺: m/z=427.3; found 427.3.

Step 2:1-{[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 93 starting from allyl({4-[(cyclohexyloxy)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamateinstead of allyl({4-[(cyclobutylmethoxy)methyl]piperidin-4-yl}methyl)[(1R,2S)-2-phenylcyclopropyl]carbamate.The reaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₄₃N₂O₃ [M+H]⁺: m/z=455.3; found 455.3.

Example 961-{[4-[(5-fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

Step 1: (5-fluoropyridin-2-yl)methyl methanesulfonate

Methanesulfonyl chloride (0.91 mL, 12 mmol) was added to a mixture of(5-fluoropyridin-2-yl)methanol (Pharmablock, cat#PB 112906) (1.00 g,7.87 mmol), and N,N-diisopropylethylamine (2.0 mL, 12 mmol) in methylenechloride (20 mL) at 0° C. The reaction mixture was stirred at roomtemperature overnight, and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel column(gradient elution with ethyl acetate in hexanes (0-55%)) to afford thedesired product (0.63 g, 39%). LC-MS calculated for C₇H₉FNO₃S [M+H]⁺:m/z=206.0; found 206.1.

Step 2:1-{[4-[(5-fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 31, with (5-fluoropyridin-2-yl)methyl methanesulfonate replacingα-bromo-4-fluorotoluene in Step 1. The reaction mixture was purifiedwith prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₆H₃₃FN₃O₂ [M+H]⁺:m/z=438.3; found 438.2.

Example 971-{[4-[(5-fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 32 and Example 31, with (5-fluoropyridin-2-yl)methylmethanesulfonate replacing α-bromo-4-fluorotoluene in Step 1 of Example31. The reaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₃₅FN₃O₂ [M+H]⁺: m/z=452.3; found 452.2.

Example 981-{[4-(4-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyll]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid

This compound was prepared using similar procedures as described forExample 31, with p-methoxybenzyl chloride replacingα-bromo-4-fluorotoluene in Step 1. The reaction mixture was purifiedwith prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₈H₃₇N₂O₃ [M+H]⁺:m/z=449.3; found 449.2.

Example 991-{[4-(4-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid

This compound was prepared using similar procedures as described forExample 32 and Example 31 with p-methoxybenzyl chloride replacingα-bromo-4-fluorotoluene in Step 1 of Example 31. The reaction mixturewas purified with prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₉H₃₉N₂O₃ [M+H]⁺:m/z=463.3; found 463.3.

Example 100(trans-4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclohexyl)methanol

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(33 mg, 0.075 mmol) was added to a mixture of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 20 mg, 0.06 mmol),trans-4-(hydroxymethyl)cyclohexanecarboxylic acid (TCI America,cat#H1243: 13 mg, 0.080 mmol) in acetonitrile (1.0 mL), followed by theaddition of triethylamine (26 μL, 0.18 mmol). The reaction mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith saturated aqueous NaHCO₃, and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude2,2,2-trifluoro-N-((1-(4-(hydroxymethyl)-cyclohexanecarbonyl)-4-(methoxymethyl)piperidin-4-yl)methyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamidewas dissolved in THF (1 mL) then 2N NaOH (1 mL) was added. The reactionmixture was stirred at 60° C. for 2 h. After cooling to roomtemperature, the organic phase was separated, acidified with TFA, andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to afford thedesired product as TFA salt. LC-MS calculated for C₂₅H₃₉N₂O₃ [M+H]⁺:m/z=415.3; found 415.3.

Example 101(cis-4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclohexyl)methanol

This compound was prepared using similar procedures as described forExample 100 with cis-4-(hydroxymethyl)cyclohexanecarboxylic acid (TCIAmerica, cat#H1242) replacingtrans-4-(hydroxymethyl)cyclohexanecarboxylic acid. The reaction mixturewas purified with prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₅H₃₉N₂O₃ [M+H]⁺:m/z=415.3; found 415.3.

Example 1021-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclopropanecarbonitrile

This compound was prepared using similar procedures as described forExample 100 with 1-cyanocyclopropanecarboxylic acid (Aldrich,cat#343390) replacing trans-4-(hydroxymethyl)cyclohexanecarboxylic acid.The reaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₃₀N₃O₂ [M+H]⁺: m/z=368.2; found 368.1.

Example 1032-(4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)ethanol

Step 1:2,2,2-trifluoro-N-{[4-(methoxymethyl)-1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide

N,N-Diisopropylethylamine (0.59 mL, 3.4 mmol) was added to a mixture of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 0.50 g, 1.3 mmol), 1H-pyrazole-4-carboxylic acid(Ark Pharm, cat#AK-25877: 0.18 g, 1.6 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.71 g, 1.6 mmol) in acetonitrile (5 mL). The reaction mixture wasstirred at room temperature overnight, and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column (gradient elution with 0 to 5% MeOH in DCM) to afford thedesired product. LC-MS calculated for C₂₃H₂₈F₃N₄O₃ [M+H]⁺: m/z=465.2;found 464.9.

Step 2:2-(4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)ethanol

A mixture of2,2,2-trifluoro-N-{[4-(methoxymethyl)-1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(50. mg, 0.11 mmol), 2-Bromoethanol (30 mg, 0.2 mmol), Cesium Carbonate(70. mg, 0.22 mmol) in N,N-dimethylformamide (1.5 mL) was heated at 100°C. overnight. The reaction mixture was cooled to room temperature thenquenched with saturated aqueous NaHCO₃, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crude2,2,2-trifluoro-N-((1-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-4-(methoxymethyl)piperidin-4-yl)methyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamidewas dissolved in THF (2 mL) then 2N NaOH (2 mL) was added. The reactionmixture was stirred 80° C. for 2h. The reaction mixture was cooled toroom temperature, then diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₃H₃₃N₄O₃ [M+H]⁺:m/z=413.3; found 413.0.

Example 104(1R,2S)—N-{[1-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]carbonyl}-4-(methoxymethyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine

This compound was prepared using similar procedures as described forExample 103 with 1-bromo-2-methoxyethane replacing 2-bromoethanol inStep 2. The reaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₅N₄O₃ [M+H]⁺: m/z=427.3; found 427.0.

Example 105(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]lpiperidin-4-yl}methyl)-2-phenylcyclopropanamine

This compound was prepared using similar procedures as described forExample 103 with methyl iodide replacing 2-bromoethanol in Step 2. Thereaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₃₁N₄O₂ [M+H]⁺: m/z=383.2; found 383.2.

Example 1063-(4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)propanenitrile

The reaction mixture of2,2,2-trifluoro-N-{[4-(methoxymethyl)-1-(1H-pyrazol-4-ylcarbonyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 103, Step 1: 30. mg, 0.064 mmol) and 2-propenenitrile (4.5 mg,0.084 mmol) in acetonitrile (1.0 mL) was stirred at 80° C. for 2 days.The reaction mixture was cooled to room temperature, diluted with waterand then extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crudeN-((1-(1-(2-cyanoethyl)-1H-pyrazole-4-carbonyl)-4-(methoxymethyl)piperidin-4-yl)methyl)-2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamidewas dissolved in MeOH (1 mL) and THF (1 mL) then a solution of lithiumhydroxide, monohydrate (0.0083 g, 0.20 mmol) in water (1 mL) was added.The resultant reaction mixture was stirred at 60° C. overnight thencooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₂N₅O₂ [M+H]⁺: m/z=422.3; found 422.2.

Example 1073-(3-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)propanenitrile

This compound was prepared using similar procedures as described forExample 106 and Example 103, Step 1 with 1H-pyrazole-3-carboxylic acidreplacing 1H-pyrazole-4-carboxylic acid in Step 1 of Example 103. Thereaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₃₂N₅O₂ [M+H]⁺: m/z=422.3; found 422.2.

Example 1082-(3-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)ethanol

This compound was prepared using similar procedures as described forExample 103 with 1H-pyrazole-3-carboxylic acid replacing1H-pyrazole-4-carboxylic acid. The reaction mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₃H₃₃N₄O₃ [M+H]⁺: m/z=413.3; found413.2.

Example 109(3R)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}piperidin-3-ol

Phosgene (15 wt % in toluene, 80 μL, 0.1 mmol) was added to a mixture of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 30 mg, 0.08 mmol) and triethylamine (30 μL, 0.2mmol) in acetonitrile (1.2 mL) at 0° C. The resulting reaction mixturewas stirred at room temperature for 1 h, then concentrated under reducedpressure. The crude4-(methoxymethyl)-4-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carbonylchloride was dissolved in acetonitrile (1 mL) then (3R)-piperidin-3-ol(PharmaBlock, cat#PB00798: 12 mg, 0.12 mmol) and triethylamine (20 μL,0.2 mmol) were added. The reaction mixture was stirred at roomtemperature for 30 min then 2N NaOH (1 mL) was added. The reactionmixture was stirred at 60° C. for 1 h then cooled to room temperatureand purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₃H₃₆N₃O₃ [M+H]⁺:m/z=402.3; found 402.3.

Example 110(3S)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}piperidin-3-ol

This compound was prepared using similar procedures as described forExample 109 with (3S)-piperidin-3-ol (PharmaBlock, cat#PB00799)replacing (3R)-piperidin-3-ol. The reaction mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₃H₃₆N₃O₃ [M+H]⁺: m/z=402.3; found402.2.

Example 1111-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}azetidin-3-ol

This compound was prepared using similar procedures as described forExample 109 with azetidin-3-ol hydrochloride (Oakwood, cat#013898)replacing (3R)-piperidin-3-ol. The reaction mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₁H₃₂N₃O₃ [M+H]⁺: m/z=374.2; found374.2.

Example 1121-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}piperidin-4-ol

This compound was prepared using similar procedures as described forExample 109 with 4-hydroxypiperidine (Aldrich, cat#128775) replacing(3R)-piperidin-3-ol. The reaction mixture was purified with prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₃H₃₆N₃O₃ [M+H]⁺: m/z=402.3; found 402.3.

Example 113(1R,2S)—N-({4-(methoxymethyl)-1-[(4-methoxypiperidin-1-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

This compound was prepared using similar procedures as described forExample 109 with 4-methoxypiperidine (Acros Organics, cat#39339)replacing (3R)-piperidin-3-ol. The reaction mixture was purified withprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₄H₃₈N₃O₃ [M+H]⁺: m/z=416.3; found416.3.

Example 114(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

To a solution of2,2,2-trifluoro-N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-N-[(1R,2S)-2-phenylcyclopropyl]acetamide(Example 35, Step 6: 30 mg, 0.08 mmol) and N,N-diisopropylethylamine (30μL, 0.2 mmol) in acetonitrile (1.0 mL) was added1-methyl-1H-pyrazole-4-sulfonyl chloride (ChemBridge, cat#4035233: 18mg, 0.097 mmol). The reaction mixture was stirred at room temperaturefor 30 min, then quenched with saturated aqueous NaHCO₃, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude2,2,2-trifluoro-N-((4-(methoxymethyl)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamidewas dissolved in THF (1 mL) then 1.0 M Sodium hydroxide in water (1 mL,1 mmol) was added. The reaction mixture was stirred at 80° C. for 1 h,then cooled to room temperature and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₃₁N₄O₃S [M+H]⁺: m/z=419.2; found 419.2.

Example 115(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

This compound was prepared using similar procedures as described forExample 114 with 1-methyl-1H-pyrazole-5-sulfonyl chloride (MayBridge,cat CC62303) replacing 1-methyl-1H-pyrazole-4-sulfonyl chloride. Thereaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₃₁N₄O₃S [M+H]⁺: m/z=419.2; found 419.2.

Example 116(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine

This compound was prepared using similar procedures as described forExample 114 with 1-methyl-1H-pyrazole-3-sulfonyl chloride (MayBridge,cat CC48303) replacing 1-methyl-1H-pyrazole-4-sulfonyl chloride. Thereaction mixture was purified with prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₃₁N₄O₃S [M+H]⁺: m/z=419.2; found 419.1.

Example A: LSD1 Histone Demethylase Biochemical Assay

LANCE LSD1/KDM1A demethylase assay-10 μL of 1 nM LSD-1 enzyme (ENZOBML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20,25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μLcompound/DMSO dotted in black 384 well polystyrene plates. Reactionswere started by addition of 10 μL of assay buffer containing 0.4 μMBiotin-labeled Histone H3 peptide substrate:ART-K(Me1)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO: 1 (AnaSpec 64355)and incubated for 1 hour at 25° C. Reactions were stopped by addition of10 μL 1× LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with1.5 nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225nM LANCE Ultra Streptavidin (PerkinElmer TRF102) along with 0.9 mMTranylcypromine-HCl (Millipore 616431). After stopping the reactionsplates were incubated for 30 minutes and read on a PHERAstar FS platereader (BMG Labtech). Compounds having an IC₅₀ of 1 μM or less wereconsidered active. IC₅₀ data for the example compounds is provided inTable 1 (+refers to IC₅₀≦100 nM; ++refers to IC₅₀>100 nM and ≦500 nM).

TABLE 1 Example No. IC₅₀ (nM) 1 ++ 2 + 3 ++ 4 ++ 5 + 6 + 7 + 8 + 9 +10 + 11 + 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 + 23 +24 + 25 + 26 + 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 +38 + 39 + 40 + 41 + 42 + 43 + 44 + 45 + 46 + 47 + 48 + 49 + 50 + 51 +52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64 + 65 +66 + 67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 +80 + 81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 +94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 + 104 + 105 + 106 +107 + 108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 +

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: ring A is C₆₋₁₀aryl or 5-10 membered heteroaryl having carbon and 1, 2, 3 or 4heteroatoms selected from N, O, and S; ring B is 4-10 memberedheterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected fromN, O, and S; ring C is (1) C₆₋₁₀ aryl, (2) C₃₋₁₀ cycloalkyl, (3) 5-10membered heteroaryl having carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O, and S, or (4) 4-20 membered heterocycloalkyl having carbonand 1, 2, 3 or 4 heteroatoms selected from N, O, and S; wherein L issubstituted on any ring-forming atom of ring B except the ring-formingatom of ring B to which R^(Z) is bonded; L is C₁₋₄ alkylene, —C(═O)—,—C(═O)O—, —C(═O)NR⁷—, O, NR⁷, —S(O)₂—, —S(O)—, or —S(O)₂NR⁷—; each R¹ isindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN,NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); R^(Z) is H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),or S(O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- are each optionally substituted with 1, 2,3, or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); each R² is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, CN,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein each R²is substituted on any ring-forming atom of ring B except thering-forming atom of ring B to which R^(Z) is bonded; each R³ isindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); R⁴ is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR³S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄cyanoalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); R⁵ and R⁶ areeach independently selected from H, halo, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, and —(C₁₋₄ alkyl)-OR^(a4); R⁷ is H, C₁₋₄alkyl or C₁₋₄ haloalkyl; each R^(a), R^(b), R^(c), R^(d), R^(a1),R^(b1), R^(c1), R^(d1), R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3),R^(c3), and R^(d3) is independently selected from H, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- is optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4); or any R^(c) and R^(d) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4); or any R^(c1) and R^(d1) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,3-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4); or any R^(c2) and R^(d2) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl,C₁₋₆ haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl areoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4); or any R^(c3) and R^(d3) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆haloalkyl, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)C(O)OR^(a4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), and S(O)₂NR^(c4)R^(d4), wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-6 membered heteroaryl are optionally substituted by 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)C(O)OR^(a4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), andS(O)₂NR^(c4)R^(d4); each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; or any R^(c4) and R^(d4) together withthe N atom to which they are attached form a 3-, 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy; each R^(e), R^(e1),R^(e2), R^(e3), R^(e4), and R^(e5) is independently selected from H,C₁₋₄ alkyl, and CN; each R^(a5), R^(b5), R^(c5), R^(d5) is independentlyselected from H and C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from halo, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)C(O)OR^(a6), C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), andS(O)₂NR^(c6)R^(d6); each R^(a6), R^(b6), R^(c6), and R^(d6) isindependently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl, wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; each R^(e6) is independently selectedfrom H, C₁₋₄ alkyl, and CN; m is 0, 1, or 2; n is 0, 1, 2, or 3; p is 0,1, 2, or 3; and q is 0, 1, or 2; wherein when ring B is 6-memberedheterocycloalkyl, q is 0, and L is S(O)₂, then ring C is other thanthienyl; and wherein when ring B is 5-6 membered heterocycloalkyl, A isphenyl, q is 1 or 2, and R⁴ is halo, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₁₋₆ haloalkyl, 5-10 membered heteroaryl, CN, OR^(a3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3),or S(O)₂R^(b3), then R^(Z) is not H or C(O)OR^(a1). 2-3. (canceled) 4.The compound of claim 1 having Formula IIIa or IIIb:

or a pharmaceutically acceptable salt thereof, wherein: wherein each R²is substituted on any ring-forming carbon atom of the azetidine ringdepicted in Formula IIIa or the piperidine ring depicted in Formula IIIbexcept the ring-forming carbon atom to which R^(Z) is bonded; wherein inFormula IIIb when q is 0 and L is S(O)₂, then ring C is other thanthienyl. 5-9. (canceled)
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein n is
 0. 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein n is
 1. 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein n is
 2. 13. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein each R¹ isindependently selected from halo and —O—(C₁₋₆ alkyl).
 14. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR¹ is independently selected from F and methoxy.
 15. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein both R⁵and R⁶ are H.
 16. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ and R⁶ are each independentlyselected from H and C₁₋₄ alkyl.
 17. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is H and R⁶ ismethyl.
 18. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein L is —(CH₂)_(r)—, —C(═O)—, —C(═O)NR⁷—, or —S(O)₂—,wherein r is 1, 2, 3, or
 4. 19. (canceled)
 20. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein L is —CH₂—.21-25. (canceled)
 26. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein ring C is cyclobutyl. 27-38. (canceled)39. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(Z) is H, C₁₋₄ alkyl, or C₆₋₁₀ aryl-C₁₋₄ alkyl-, or(5-10 membered heteroaryl)-C₁₋₄ alkyl-, wherein said C₁₋₄ alkyl, C₆₋₁₀aryl-C₁₋₄ alkyl- and (5-10 membered heteroaryl)-C₁₋₄ alkyl- are eachoptionally substituted by CN, halo, OR^(a1), C(O)OR^(a1), or C₁₋₄cyanoalkyl.
 40. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(Z) is H, C₁₋₄ alkyl, or C₆₋₁₀aryl-C₁₋₄ alkyl-, wherein said C₁₋₄ alkyl and C₆₋₁₀ aryl-C₁₋₄ alkyl- areeach optionally substituted by CN, halo, OR^(a1), or C₁₋₄ cyanoalkyl.41. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(Z) is C₁₋₄ alkyl.
 42. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(Z) is C₆₋₁₀aryl-C₁₋₄ alkyl-substituted by fluoro or cyanomethyl.
 43. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R^(Z)is C₁₋₄ alkyl substituted by methoxy or CN.
 44. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R^(Z) is (5-10membered heteroaryl)-C₁₋₄ alkyl-substituted by methoxy or F.
 45. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R^(Z) is H, methyl, cyanomethyl, methoxymethyl,4-fluorophenylmethyl or 4-(cyanomethyl)phenylmethyl.
 46. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(Z) isH, methyl, cyanomethyl, methoxymethyl, ethoxymethyl,4-fluorophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl,3-carboxyphenylmethyl, 6-methoxypyridin-3-yl)methyl,4-cyano-2-fluorobenzyl, (benzyloxy)methyl, (cyclobutylmethoxy)methyl,(cyclohexyloxy)methyl, (5-fluoropyridin-2-yl)methyl,4-methoxyphenylmethyl, (2-fluorophenoxy)methyl, (3-fluorophenoxy)methyl,(2-cyanophenoxy)methyl, (3-cyanophenoxy)methyl, (4-cyanophenoxy)methyl,(4-cyano-2-fluorophenoxy)methyl, (5-fluoropyridin-2-yl)oxymethyl,(5-fluoropyrimidin-2-yl)oxymethyl, (3-fluoropyridin-2-yl)oxymethyl,(6-(methylaminocarbonyl)pyridin-3-yl)oxymethyl,(6-(methylaminocarbonyl)pyridin-2-yl)oxymethyl, or4-(cyanomethyl)phenylmethyl.
 47. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(Z) is H or C₁₋₄alkyl substituted by CN.
 48. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(Z) is cyanomethyl.49. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(Z) is methoxymethyl. 50-52. (canceled)
 53. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,having a trans configuration with respect to the di-substitutedcyclopropyl group depicted in Formula I.
 54. The compound of claim 1selected from:4-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)methyl]benzoicacid;N-{[1-(4-Fluorobenzyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine;4-({4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}methyl)benzoicacid;3-({4-[(trans-2-Phenylcyclopropyl)amino]piperidin-1-yl}methyl)benzoicacid; 1-(4-Fluorobenzyl)-N-(trans-2-phenylcyclopropyl)piperidin-4-amine;4-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)methyl]benzonitrile;3-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)methyl]benzonitrile;(1-(3-Fluorobenzoyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile;(1-(3-Fluorobenzyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile;(5R)-2-(cis-4-Hydroxycyclohexyl)-7-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one;(5S)-2-(cis-4-Hydroxycyclohexyl)-7-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]-2,7-diazaspiro[4.5]decan-1-one;1-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]piperidine-4-carbonitrile;Trans-2-phenyl-N-[(1-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}azetidin-3-yl)methyl]cyclopropanamine;N-({1-[(3-Phenoxypiperidin-1-yl)carbonyl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine;N-({1-[(3-Methoxypiperidin-1-yl)carbonyl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine;4-Phenyl-1-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]piperidine-4-carbonitrile;4-Phenyl-1-[(3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]piperidin-4-ol;N-({1-[(5-Fluoro-1,2-dihydro-spiro[indole-3,4′-piperidin]-1′-yl)carbonyl]azetidin-3-yl}methyl)-trans-2-phenylcyclopropanamine;N-(2-Fluorophenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide;N-(3-Fluorophenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide;N-(4-Fluorophenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide;N-(4-Methoxyphenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide;N-(3-Methoxyphenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide;N-(2-Methoxyphenyl)-3-{[(trans-2-phenylcyclopropyl)amino]methyl}azetidine-1-carboxamide;4-[(3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]benzonitrile;3-[3-{[(trans-2-Phenylcyclopropyl)amino]methyl}azetidin-1-yl)carbonyl]benzonitrile;N-{[1-(3-Methoxybenzoyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine;N-{[1-(4-Fluorobenzoyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine;N-{[1-(3-Fluorobenzoyl)azetidin-3-yl]methyl}-trans-2-phenylcyclopropanamine;andTrans-2-phenyl-N-[(1-{[4-(trifluoromethoxy)phenyl]sulfonyl}azetidin-3-yl)methyl]cyclopropanamine;or a pharmaceutically acceptable salt of any of the aforementioned. 55.The compound of claim 1 selected from:1-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;trans-4-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclohexanamine;1-{[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclobutanamine;1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylicacid;(1R,2S)—N-[(4-(methoxymethyl)-1-{[(2S)-1-methylpyrrolidin-2-yl]carbonyl}piperidin-4-yl)methyl]-2-phenylcyclopropanamine;(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-imidazol-4-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;6-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyridazin-3-amine;(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methylpiperidin-4-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-3-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-({4-(methoxymethyl)-1-[(4-methylpiperazin-1-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;1-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;(1R,2S)—N-({4-methyl-1-[(1-methyl-1H-pyrazol-3-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-({4-methyl-1-[(1-methyl-1H-imidazol-4-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;5-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyrimidin-2-amine;6-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyridazin-3-amine;4-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-3-amine;1-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclopentanamine;5-{[4-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}pyrimidin-2-amine;1-{[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid; or a pharmaceutically acceptable salt of any one of theaforementioned.
 56. The compound of claim 1 selected from:(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-({4-(methoxymethyl)-1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-({4-(methoxymethyl)-1-[(4-methoxypiperidin-1-yl)carbonyl]piperidin-4-yl}methyl)-2-phenylcyclopropanamine;(1R,2S)—N-{[1-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]carbonyl}-4-(methoxymethyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;(3R)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}piperidin-3-ol;(3S)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}piperidin-3-ol;(3S)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyrrolidin-3-ol;(cis-4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclohexyl)methanol;(trans-4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclohexyl)methanol;1-{[4-({[(1R,2S)-2-(2-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl})cyclobutanecarboxylicacid;1-{[4-({[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl})cyclobutanecarboxylicacid;1-{[4-({[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl})cyclobutanecarboxylicacid;1-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-(4-cyano-2-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-(4-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-(4-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-(4-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}azetidin-3-ol;1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}cyclopropanecarbonitrile;1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}piperidin-4-ol;1-{[4-(methoxymethyl)-4-({[2-(2-methoxyphenyl)cyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-(methoxymethyl)-4-({[2-(4-methoxyphenyl)cyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-(methoxymethyl)-4-(1-{[(1R,2S)-2-phenylcyclopropyl]amino}ethyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[({6-[(methylamino)carbonyl]pyridin-2-yl}oxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[({6-[(methylamino)carbonyl]pyridin-3-yl}oxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(2-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(2-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(3-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(3-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(3-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(3-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(4-cyano-2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(4-cyano-2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(4-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(4-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(5-fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(5-fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(6-methoxypyridin-3-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(benzyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(benzyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylicacid;1-{[4-{[(3-fluoropyridin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;1-{[4-{[(5-fluoropyrimidin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopropanecarboxylicacid;2-(3-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)ethanol;2-(4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)ethanol;3-(3-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)propanenitrile;3-(4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}-1H-pyrazol-1-yl)propanenitrile;3-{[1-(3-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoicacid;3R)-1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]carbonyl}pyrrolidin-3-ol;4-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}benzoicacid; andtrans-4-{[4-(3-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclohexanecarboxylicacid; or a pharmaceutically acceptable salt of any one of theaforementioned.
 57. A pharmaceutical composition comprising a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and at leastone pharmaceutically acceptable carrier.
 58. The pharmaceuticalcomposition of claim 57, further comprising another therapeutic agent.59. A method of inhibiting LSD1 comprising contacting a compound ofclaim 1, or a pharmaceutically acceptable salt thereof, with said LSD1.60. A method of inhibiting LSD1 comprising contacting the pharmaceuticalcomposition of claim 57 with said LSD1.
 61. A method of treating adisease comprising administering to a patient a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein said disease is cancer. 62-65.(canceled)
 66. A method of treating a disease comprising administeringto a patient a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof, wherein said diseaseis a viral disease or a beta-globinopathy.
 67. (canceled)